Relatório Anual 2010

Transcrição

Relatório Anual
2010
ÍNDICE
1 NOTA INTRODUTÓRIA 3
2 CHAMPALIMAUD CENTRE FOR THE UNKNOWN
7
2.1 Infra-estrutura
2.1.1 Edifícios e arranjos exteriores
2.1.2 Equipamento clínico
2.1.3 Mobiliário
2.1.4 Sistemas de Informação
2.1.5 Inauguração
2.1.5 O Centro
3 PROGRAMA CHAMPALIMAUD DE NEUROCIÊNCIAS
3.1 Programa Champalimaud de Neurociências no Instituto Gulbenkian de Ciência
3.2 Neuroscience Lecture
4 PROGRAMA DE CANCRO
4.1 Programa Doutoral para Médicos
4.2 Simpósios e Reuniões
5 PRÉMIO ANTÓNIO CHAMPALIMAUD DE VISÃO
5.1 Reunião do Júri e selecção dos premiados
5.2 Cerimónia de atribuição do Prémio
5.3 Preparação do Prémio 2011
5.4 Conferência sobre o Prémio António Champalimaud de Visão na ARVO
5.5 ARVO Foundation Host-a-Researcher Programme
6 REDE C-TRACER
6.1 C-TRACER – Índia
6.2 C- TRACER – Coimbra
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4.2.1 2010 Champalimaud Cancer Centre Symposium
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7 OUTRAS PARCERIAS
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7.1 Health Cluster Portugal
8 PROGRAMA CHAMPIMÓVEL 8.1 Introdução
8.2 Objectivos
8.3 Protocolos
8.4 Eventos
8.5 Roteiro
8.6 Sessões e visitas
8.7 Reuniões
8.8 Divulgação
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9 REUNIÕES DA FUNDAÇÃO
9.1 Conselho de Curadores
9.2 Conselho Cientifico
10 COMUNICAÇÃO E PATROCÍNIOS
10.1 “730 Dias” num livro
10.2 Fotografias
10.3 Patrocínios
11 GESTÃO DO PATRIMÓNIO FINANCEIRO
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120
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1 NOTA INTRODUTÓRIA
O Centro de Investigação Champalimaud transformou-se de sonho
em realidade.
Cumpridos prazos muito exigentes, o complexo físico que dá corpo à
Fundação e abrigo aos nossos investigadores foi inaugurado no dia 5 de
Outubro de 2010, tal como previsto desde o início do seu lançamento.
No princípio de 2010, os edifícios ainda eram esqueletos, erguidos mas
não preenchidos, com as paredes exteriores a serem revestidas, mas
contendo ainda largos espaços interiores cujos contornos eram difíceis
de discernir.
Mas, no dia 5 de Outubro, os edifícios estavam erguidos e completados, seguros de força e de elegância, traduzindo na sua esplêndida
arquitectura os conceitos cívico e científico que tinham presidido
à sua concepção.
Foi, para a Fundação Champalimaud, uma honra que a inauguração
Leonor Beleza
Presidente da Fundação Champalimaud
do seu complexo tenha sido inserida nas comemorações oficiais do
Centenário da República Portuguesa. Para todos nós, os milhares de
pessoas envolvidos na sua construção, constitui motivo de grande
satisfação que essa inauguração tenha ocorrido no tempo e no
orçamento desde o início previstos.
O ano de 2010 ficará assim na história da Fundação como aquele em
que adquiriu um corpo físico com que ficará doravante identificada.
E como o momento em que demonstrámos para nós próprios que
muito trabalho, aliado a uma rigorosa programação, resulta na realização
de “milagres”.
O Centro de Investigação Champalimaud foi concebido e executado
como uma grande peça de arquitectura e um espaço de pertença da
comunidade. Erguido numa zona privilegiada da cidade de Lisboa,
junto ao rio, cheia da História do nosso País, ele tinha de se distinguir
pela qualidade física da sua presença e pela capacidade de oferecer aos cidadãos espaços e experiências.
Mas ele convida também a partilhas num sentido mais especificamente
importante para o tipo de ciência que nele será produzido: a concepção
de laboratórios e de serviços, de áreas comuns e de zonas mais
protegidas, pretende induzir uma proximidade entre investigadores
FC Relatório Anual 2010
e médicos, doentes, famílias e profissionais, por forma a que a noção
da presença de cada um dos grupos de insinue nas preocupações
e nas experiências fecundas de cada um.
Fazer ciência de translação, que se traduza em benefícios efectivos
na prevenção e no tratamento das doenças, é o nosso objectivo
fundamental, que colhemos na nossa percepção do que era a vontade
do nosso Fundador. Por isso, o Centro foi concebido e executado
de forma a permitir um intenso convívio de cientistas e cuidadores, e
mesmo a confusão em muitos deles das duas qualidades.
Por outro lado, a presença no mesmo espaço de doentes e de cientistas,
que não vimos executada ainda em nenhum lado, permitirá transmitir
um sentido de urgência ao encontrar de soluções para problemas
ainda hoje não resolvidos.
A inauguração do complexo ocorreu portanto num dia muito especial.
Pusemos também na sua preparação o maior dos cuidados. Quisemos
que a cerimónia constituísse um momento solene de homenagem ao
nosso Fundador e de celebração para todos os que participaram na
concretização do que pensamos ter constituído parte do seu sonho.
Fizemos questão de que estivessem presentes, num momento tão
especial, muitos dos Amigos da Fundação que nos têm ajudado nas
escolhas e nas realizações.
Concebemos aqueles momentos especiais para neles traduzirmos
a ambição que anima o nosso projecto, o carácter profundamente
português que nos corre na alma e as nossas ligações do passado
como inspiração para a construção do futuro.
A cerimónia foi presidida pelo Presidente da República, e nela estiveram
presentes o Primeiro-Ministro, o Presidente da Câmara Municipal de
Lisboa, o Presidente do Conselho Científico e Prémio Nobel, James
Watoson, o Arquiteto que concebeu o Centro, Charles Correa, o
Cardeal-Patriarca e muitas personalidades.
É claro que o ano de 2010 foi ocupado no essencial com o trabalho
de concluir a construção do Centro Champalimaud, e, logo a seguir
à inauguração dos edifícios, dedicado a um sem-número de tarefas
de carácter técnico e administrativo, envolvendo licenciamentos,
aquisição e desenvolvimento de equipamentos e sistemas, testes de
todos os tipos e montagem dos serviços clínicos e dos laboratórios.
Queremos, como é óbvio, ocupar e pôr em funcionamento o Centro
com a brevidade possível.
O Programa Champalimaud de Neurociências prosseguiu a sua actividade e desenvolveu-se durante o ano de 2010. Em Dezembro, estavam
nele activas muitas dezenas de cientistas a trabalhar em investigação
de ponta e pessoas na área de tomada de decisão. Mantiveram-se
durante o ano de 2010 alojadas no Instituto Gulbenkian de Ciência
e constituirão os primeiros laboratórios a ocupar progressivamente
o novo edifício, ao ritmo e na medida em que os respectivos projectos
de investigação o forem permitindo.
Vimos, com grande satisfação, o nosso Conselho Científico manifestar
significativo apreço pelos projectos e pelas realizações do Programa, e
pela respectiva coesão.
Prosseguiu, em 2010, a montagem do nosso programa de investigação
em cancro. Concentrámos, numa primeira fase, a nossa atenção na
construção da vertente clínica, decisiva para o desenvolvimento
da investigação tal como a concebemos, centrada na tradução de
conhecimentos em melhor prevenção e melhor tratamento da doença. Juntámos à cerimónia da inauguração a da atribuição do Prémio
António Champalimaud de Visão, neste ano tão especial da vida da
Fundação. O prémio foi para os laboratórios de Anthony Movshon e de
William Newsome, dois neurocientistas que, em parte separadamente,
e em parte em conjunto, contribuíram para desvendar o papel do
nosso cérebro na elaboração e na utilização de dados inseridos na
nossa visão.
Prosseguimos e aumentámos as operações do nosso Champimóvel,
que continua a percorrer o País e a tentar despertar nas crianças e nos
jovens o interesse científico.
O C-TRACER, em Hyderabad, continua o seu caminho no domínio
da aplicação de conhecimentos de ponta para devolver a visão a
pessoas dela privadas. E foi reconhecida como C-TRACER 2 a AIBILI,
Associação para a Investigação Biomédica e Inovação em Luz e
Imagem, de Coimbra, que, sob a direcção do Prof. José Cunha Vaz,
desenvolve investigação translacional e coordena uma rede europeia
de ensaios clínicos, e que se associa assim à Fundação e ao nosso
programa na Índia.
Mantendo o hábito de reforçar a nossa rede de Amigos por altura do
Natal, promovemos e enviámos-lhes, desta feita, a obra 730 dias, de
Rui Ochôa, um acervo de belíssimas fotografias que documentam o
processo de construção do nosso Centro, afinal tão rápido (durou 730
dias). Antes do seu início, e durante toda a construção, foi recolhida
documentação gráfica, em fotografias e em filme, que permite guardar
memórias fundamentais do nosso percurso. Este livro corresponde
a uma primeira utilização sistematizada desse acervo e permitiu-nos
contar em imagens um pouco do que aconteceu.
Do ponto de vista dos mercados financeiros e da gestão do nosso
património, o ano de 2010 terminou de forma bastante positiva,
apesar da irregularidade com que se foi desenvolvendo. Consolidada
a nossa determinação em nos tornarmos progressivamente menos
dependentes do portefólio financeiro, agora que no nosso património
se solidificaram bens que nos permitem uma mais eficaz diversificação
de fontes de meios, trabalhámos para procurar essas outras fontes.
E mantemos um enorme rigor na utilização de meios, fazendo uso da
maior parcimónia na contratação, em termos de números, como em
termos de prazos.
Finalmente, uma palavra de profundo reconhecimento a todos que, de
dentro e de fora, nos ajudaram a chegar aqui. E uma ainda, de desejo
profundo de que nos não falte a força e o estímulo para realizar o sonho
de António Champalimaud. FC Relatório Anual 2010
2 CHAMPALIMAUD CENTRE
FOR THE UNKNOWN
2.1 Infra-estrutura
2.1.1 Edifícios e arranjos exteriores
2.1.2 Equipamento clínico
2.1.3 Mobiliário
2.1.4 Sistemas de Informação
2.1.5 Inauguração
2.1.6 O Centro
2 CHAMPALIMAUD CENTRE FOR
THE UNKNOWN
Trabalhos de finalização do Centro
2.1Infra-estrutura
2.1.1Edifícios e arranjos exteriores
Durante o ano de 2010 foram concluídos os trabalhos de construção do Centro
de Investigação Champalimaud, concretamente a sua fase de execução das
especialidades e dos acabamentos, que teve início em Outubro de 2009.
Tal como nas fases anteriores, estes trabalhos foram executados pelo consórcio Mota-Engil/HCI e fiscalizados pela Consulgal e foram acompanhados pelo
Arquitecto Charles Correa, por todos os projectistas, nomeadamente a RMJM/
Hillier e a Vanderweil, e pela Glintt, responsável pela gestão do projecto.
São de realçar pela sua complexidade o fabrico e a montagem das cortinas
de vidro e a instalação de muitas infra-estruturas técnicas.
Para além da conclusão da arquitectura e das especialidades dos edifícios,
foi também concluída a ponte de vidro que liga os edifícios, construída pela
empresa espanhola Bellapart de acordo com o projecto da firma alemã
Schlaich Bergermann und Partner.
Finalmente, foi produzida e instalada a sinalética exterior e interior dos edifícios,
de acordo com o projecto da firma holandesa Studio Dumbar, em colaboração
com a empresa alemã Unit Design.
Todos os trabalhos decorreram a um ritmo intenso, para serem respeitados
os prazos previstos, assegurando a inauguração do Centro de Investigação
Champalimaud na data prevista de 5 de Outubro de 2010, no âmbito das
comemorações do centenário da implantação da República.
É digno de destaque o cuidado extremo com a segurança da obra, o que
Edifício A, trabalhos de revestimento
em pedra
permitiu que entre as largas centenas de trabalhadores envolvidos na
construção do Centro, não fossem registados quaisquer acidentes durante
toda a obra.
2.1.2Equipamento clínico
Foram adjudicados e instalados equipamentos de diagnóstico por imagem e
de radioterapia.
Os equipamentos de imagiologia foram adjudicados à Philips e incluíram
equipamentos de radiologia convencional e de ultra-sonografia, de tomografia
axial computorizada (TAC), de ressonância magnética e de medicina nuclear,
concretamente uma Câmara Gama e um PET-CT.
O equipamento de radioterapia inclui um acelerador linear “Elekta”, de última
geração.
Ainda durante o ano de 2010 foram iniciados os testes com vista ao
licenciamento e ao commissioning dos equipamentos, que deverá estar
concluído no primeiro semestre de 2011.
Celebração da conclusão da obra, Outubro 2010
2.1.3Mobiliário
Imediatamente antes da inauguração do Centro de Investigação Champalimaud
foi iniciada a instalação do mobiliário, que se manterá de forma incremental
durante a entrada em funcionamento das áreas clínicas e de investigação.
2.1.4Sistemas de Informação
A infra-estrutura de sistemas de informação e de comunicação, bem como
a sua arquitectura e aplicações foi desenhada e começou a ser instalada
em 2010, de forma a garantir o suporte necessário para as actividades de Mobiliário de laboratório
investigação e para a prestação de cuidados de saúde oncológicos.
10
Inauguração da Fundação Champalimaud,
5 de Outubro de 2010
2.1.5Inauguração
No dia 5 de Outubro, foi inaugurado o novo edifício que acolhe o Centro de
Investigação da Fundação Champalimaud, cumprindo assim o compromisso
assumido para a concretização deste projecto inserido nas comemorações
oficiais do Centenário da República Portuguesa.
A Fundação acolheu nas suas novas instalações muitos colaboradores e
amigos que ao longo dos anos foram contribuindo de forma empenhada
para a concretização do seu objectivo de construção de um centro de
investigação científico multidisciplinar, translacional e de referência no campo
da biomedicina.
Inscrição inaugural pela Presidente
da Fundação Champalimaud,
Leonor Beleza
A cerimónia foi presidida pelo Presidente da República, Prof. Doutor Aníbal
Cavaco Silva, e estiveram presentes o Primeiro-Ministro, Eng. José Sócrates,
muitas outras individualidades de diversos sectores da vida política, económica, e social, diplomatas acreditados em Portugal, titulares dos órgãos da
Fundação, e membros da família do Fundador, entre os muitos amigos que
nos acompanham desde sempre.
O magnífico complexo inaugurado e o enquadramento histórico e ambiental
único que o rodeia acolheram os nossos convidados para uma celebração
que certamente ficará na memória de todos pela originalidade, beleza e
sobriedade. Como certamente não poderemos esquecer a adesão que
Benção das instalações,
sentimos nos presentes ao sentido nacional e à ambição do projecto da Cardeal Patriarca de Lisboa,
D. José Policarpo
Fundação que perpassaram aqueles momentos tão especiais.
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Uma sessão solene foi realizada em palco montado na área central, que
constitui o “passeio público”, permitindo a todos os presentes ficar à altura
do lago na parte superior. Aproveitando a ilusão de continuidade entre a água
desse lago e o Tejo e o mar, lá fora, bem como os elementos decorativos
utilizados, todos parecíamos estar sobre a imensidão do rio e do mar, imbuídos
do espírito pioneiro e da coragem ilimitada dos nossos antepassados que
de aqui partiram. O carácter nacional do dia e a presença de uma forte
representação da ciência internacional ajudaram a caracterizar a cerimónia,
bem com o projecto que o Centro de Investigação materializará.
A cerimónia incluiu uma bênção das instalações pelo Cardeal-Patriarca de Luísa Champalimaud, filha do Fundador
Lisboa, D. José Policarpo, a inscrição numa das colunas que ladeiam o
lago, à mão, de referência ao momento, pela Presidente da Fundação, e,
em seguida, intervenções da mesma, de Luísa Champalimaud, em nome da
família do Fundador, do Presidente do Conselho Científico, James Watson,
e do Arquitecto Charles Correa. Este definiu bem o pensamento subjacente
ao projecto: “Este edifício utiliza os mais altos níveis de ciência e medicina
contemporânea para ajudar as pessoas a resolverem problemas verdadeiros:
cancro, danos cerebrais, cegueira. E, para albergar estas funções, tentámos
criar uma peça arquitectónica. Arquitectura como Escultura. Arquitectura
como Beleza. Beleza como Terapia.”
A cerimónia fechou com a intervenção do Presidente da República, que
felicitou a Fundação e a incentivou a procurar os níveis científico, ético e cívico
mais elevados.
Durante o almoço que se seguiu, foi atribuído o Prémio António Champalimaud
de Ciência de 2010.
Prof. James Watson,
Presidente do Conselho Científico
da Fundação Champalimaud
Durante o dia, foram dadas a conhecer aos nossos convidados as instala
-ções da clínica e dos laboratórios, através de visitas guiadas por investigadores da Fundação.
Visita inaugural, auditório
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Arquitecto Charles Correa,
autor do projecto do Centro
2.1.6O Centro
O Centro agora inaugurado garante todas as condições para que investigadores e académicos, nacionais e estrangeiros, desenvolvam projectos de
excelência nas áreas das neurociências e da oncologia.
O Centro dispõe de excelentes condições e das mais modernas tecnologias
para investigação biomédica, bem como das infra-estruturas necessárias ao
ensino pós-graduado e a programas de mestrado e de doutoramento.
Para prosseguir estes objectivos, a Fundação optou por um modelo de investigaçãotranslacional, ou seja, fazendo permanentemente a ponte entre a
investigação básica e a investigação clínica, assegurando que as descobertas
científicas e as novas tecnologias se aplicam no desenvolvimento e no ensaio
de soluções para os problemas clinicamente relevantes. Desta ligação íntima
entre cientistas e médicos, entre investigação e tratamento, nascerá mais
rapidamente a resposta para os problemas que afligem as pessoas.
O Centro Champalimaud será usado por todos. Os jardins e restantes áreas
públicas ocupam uma parte substancial do espaço disponível. Jardins
panorâmicos com uma grande variedade de árvores e áreas verdes, um
anfiteatro ao ar livre para a realização de espectáculos musicais, sessões
científicas ou artísticas - tudo isto tendo como pano de fundo a água e o Tejo
- estão à disposição da cidade.
O seu complexo arquitectónico inclui dois edifícios dispostos de forma a
promover o livre acesso:
- Edifício A, que contém nos pisos inferiores as áreas de diagnóstico e de
tratamento, e nos pisos superiores os laboratórios de investigação.
- Edifício B, que inclui nos seus espaços públicos um auditório, uma área
de exposições e um restaurante. No piso superior estão os escritórios da
Fundação, que comunicam com o Edifício A através de uma ponte em vidro.
13
Um grande espaço aberto ao público, com jardins panorâmicos e um anfiteatro
ao ar livre completa o conjunto.
A forma tomada pelo complexo arquitectónico dispõe-se numa suave fuga
para a foz do rio Tejo, simbolizando uma procura de ”mundos desconhecidos”
e um novo encontro com a gesta dos Descobrimentos portugueses, agora
simbolicamente renovada nas actividades a desenvolver neste Centro de
Investigação de excelência. Charles Correa, arquitecto de origem goesa e
autor do projecto presta, desta forma inspirada, um tributo a Portugal e à
abertura que realizámos a novos mundos.
No coração da edifício A está localizada a actividade principal do centro,
com os centros de diagnóstico,clínico e de tratamento, e com os laboratórios
oncológico e de neurociências nos pisos superiores.
Entra-se no edifício através de um lóbi de duplo pé direito que dá para um
jardim tropical coberto. No piso da entrada encontram-se as zonas de exames,
ligadas ao apoio clínico e ao centro de bem-estar. A partir do lóbi há acesso
directo a uma área localizada no piso inferior, onde os utentes podem deixar
os seus filhos pequenos, e com abertura directa para o jardim tropical, peça
central do edifício. Neste piso estão o centro de imagiologia e o centro de
tratamento oncológico, sendo que este se abre para um outro jardim mais
calmo e reservado, na extremidade oeste e inteiramente dedicado a estes
doentes.
No primeiro piso estão localizados laboratórios de investigação, distribuídos
à volta do jardim tropical,e os gabinetes dos investigadores. Estes espaços
culminam numa biblioteca de dois pisos localizada numa posição fulcral na
intersecção das duas alas, o que a torna num local de encontro de cientistas
e de utentes.
O segundo piso é dedicado também a laboratórios, com aberturas para o piso
inferior que ligam os dois níveis, de modo a incentivar e facilitar a interacção
entre os profissionais das várias áreas de actividade do Centro de Investigação
da Fundação.
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3 PROGRAMA CHAMPALIMAUD
DE NEUROCIÊNCIAS
3.1 Programa Champalimaud de Neurociências
no Instituto Gulbenkian de Ciência
3.2 Neuroscience Lecture
3 PROGRAMA CHAMPALIMAUD
DE NEUROCIÊNCIAS
Actividade de formação na área
das Neurociências
3.1Programa Champalimaud de
Neurociências no Instituto Gulbenkian de Ciência
Foram cumpridos os objectivos e as iniciativas previstas no Protocolo de
Colaboração com a Fundação Calouste Gulbenkian/Instituto Gulbenkian de
Ciência, nomeadamente o “Programa Champalimaud em Neurociências” e o
“Programa Gulbenkian/Champalimaud de Doutoramento em Neurociências”.
A gestão e a responsabilidade científica dos Programas cabem à Direcção
do IGC e ao Coordenador do Programa de Neurociências, Doutor Zachary
Mainen, cujo relatório de actividades desenvolvidas em 2010 se encontra nas
páginas seguintes em língua inglesa.
O acompanhamento do Protocolo foi feito pelas administrações das
Fundações, que reuniram periodicamente com a Direcção do IGC.
Programa Gulbenkian/Champalimaud
de Doutoramento em Neurociências
16
3.2Neuroscience Lecture
A 6 de Outubro, teve lugar uma Lecture, organizada no âmbito do Programa
de Neurociências.
A abertura esteve a cargo do Professor António Damásio, David Dornsife
Professor of Neuroscience e Director do Brain and Creativity Institute, na
Universidade da Califórnia do Sul, e Professor Adjunto no Salk Institute em
La Jolla, California, EUA., bem como membro do Conselho de Curadores da
Fundação Champalimaud.
Seguiram-se as seguintes intervenções:
J. Anthony Movshon, Director da New York University’s Center for Neural
Studies: “Encoding and decoding of visual information by cortical
neurons”
William T. Newsome, Investigador no The Howard Hughes Medical Institute
e Professor de Neurobiologia na Standford University, EUA: “A dynamic
systems approach to visually based decision-making”
Ambos os oradores receberam o Prémio António Champalimaud de Visão em
2010.
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RESEARCH GROUPS
Megan R. Carey
Neural Circuits and Behavior
We are interested in the neural basis of behavior – how activity in neural
circuits enables us to interact appropriately with the world around us. Our
research focuses on the cerebellum, a brain area that plays a central role
in coordinated motor control and motor learning. Our goal is to understand
how cellular processes within the cerebellum contribute to specific aspects
of behavior. We use transgenic mice to specifically perturb cellular processes
in identified neuronal populations and dissect cerebellar circuit function.
Endocannabinoids in cerebellar learning
Cannabinoids are powerful neuromodulators that are responsible for the
Cerebellar circuit diagram.
The known anatomy and connectivity
of the cerebellar circuit allows us to
perturb cellular and synaptic functions of identified cell types
and assess the effects on behavior.
psychotropic effects of marijuana and mediate several forms of synaptic
plasticity. In the cerebellum, both short- and long-term plasticity between
parallel fibers and Purkinje cells depend on activation of cannabinoid
receptors (CB1Rs). Recently we have shown, using cell type-specific CB1
knockout mice, that CB1Rs on cerebellar parallel fibers are required for
this plasticity. We are now using these mice to examine the behavioral
consequences of CB1R deletion from parallel fibers. Specifically, we are
testing the hypothesis that CB1-dependent long-term depression is required
for a simple form of learning, classical eyelid conditioning.
Cellular and circuit analysis of genetic perturbations
We take advantage of the molecular identifiability and known connectivities
of cerebellar neurons to make targeted perturbations of the cerebellar circuit.
Existing technologies allow us to knock out or selectively express individual
molecules in identified cell types. We will use in vitro electrophysiology and
calcium imaging to characterize the effects of these manipulations on neural
excitability, synaptic transmission, and plasticity. Our goal is to acquire
a detailed understanding of the contribution of individual molecular and
cellular elements to overall circuit function.
Development of new behavioral assays
The cerebellum performs complex feats of motor coordination. Yet, behavioral
assessments of cerebellar circuit function in mice are typically limited either
to general measures of coordination or relatively simple forms of associative
learning. We are working to establish new, quantitative measures of cerebellar
function. By comparing specific aspects of behavior across mice in which genetic perturbations have been targeted to different individual neuronal types,
we hope to determine links between cellular and circuit function and behavior.
18
Rui M. Costa
Neurobiology of Action
Group members
Cristina Afonso (Postdoctoral Fellow)
Fatuel Aguilar (Postdoctoral Fellow)
Joana Almeida (Technician)
John Burkhardt (Postdoctoral Fellow)
Eduardo Ferreira (PhD Student)
Pedro Ferreira (PhD Student)
Catherine French (Postdoctoral Fellow)
Rosalina Fonseca (Clinical Research Fellow)
Albino Maia (Clinical Research Fellow)
Gabriela Martins (Postdoctoral Fellow)
Vítor Paixão (Postdoctoral Fellow)
Fernando Santos (PhD Student)
Ana Maria Vaz (Technician)
Ana Mafalda Vicente (PhD Student)
We study the neurobiology of action in health and disease.
To study actions is to study the way we do things, which is different than
studying how we remember stimuli, or facts and events. Some actions are
innate or pre-wired (like swallowing, breathing, even grooming). Others Specificity of Cre expression in PVCre
and ChATCre mice. (A) Montage of
are learned through trial and error throughout life. We currently focus on images from an adult brain section
through the striatum demonstrating
understanding the processes mediating the latter.
YFP colocalisation with PV in the
Our overall goal is to understand how changes in molecular networks in the PVCre mouse line crossed with a
ROSA26-YFP reporter mouse. The
brain modify neural circuits to produce experience-dependent changes in inset in dorso-lateral striatum depicts
actions. In order to understand how actions are learned through trial and the location from where the smaller
images were obtained (B-G). (B-D)
error, we subdivided our experiments in different components, or specific The first column demonstrates
goals:
Action initiation: how do we initiate and generate diverse actions (trial),
Action improvement: how do we improve the accuracy and speed of actions
(through trial and error)
Actions and outcomes: how do we learn that particular actions lead to particular
outcomes (goal of the action) and how do we form habits.
PV immuno-reactivity (in red; B),
YFP expression (green; C), and
colocalisation of both (yellow; D)
in the PVCre-ROSA-YFP mouse
striatum. (E-G) The second panel
shows ChAT immuno-reactivity (in
red; E), YFP expression (green, F),
and colocalisation of both (yellow;
G) in a ChATCre-ROSA-YFP mouse
striatum. Scale bars = (A) 500µm;
(D) 125µm for (B-G).
(Gabriela Martins)
A growing body of evidence supports an important role of the basal ganglia in
action initiation and selection, in skill learning, and in learning goal-directed
actions and habits. Therefore, we centered our efforts on investigating the
cortico-basal ganglia mechanisms underlying these three processes using
an across-level approach, from molecules to circuits.
We chose to implement this integrative approach in mice because they
combine the power of genetics, a mammalian brain with canonical cortico-
19
-basal ganglia loops that can generate and propagate oscillatory activity,
and the possibility of accurately quantifying simple behaviours like action
initiation (with EMG recordings or using inertial sensors) and stereotypic
skill learning, and more elaborate behaviours like goal-directed actions.
Our research programme will hopefully shed light on the mechanisms
underlying the diversity of actions we perform, the automatisation of actions
and the generalisation of rules or ways to carry them out. Our research may
also have important implications for understanding the relation between
corticostriatal dysfunction and the symptoms of different neurodegenerative
and psychiatric disorders.
Neural mechanisms of skill and sequence learning
Understanding how novel actions are learned and consolidated as sequences
of movements and skills are the main aims of this project.
In the past year we have uncovered neural activity in nigrostriatal circuits
related to the initiation and termination of novel action sequences.
Corticostriatal mechanisms underlying goal-directed actions and habits
Our goal is understanding the difference in the brain between intentional
actions and habits or routines.
In 2010 we discovered that uncertainty increases the propensity for habit
formation and investigated the relation between medial and lateral striatal
circuits in controlling goal-directed actions versus habits and found that SNc
but not VTA dopaminergic neurons are involved in habits.
Neural mechanisms underlying the generation of novel actions
This project aims to understand how new self-initiated actions are generated
and how this ability is hampered in Parkinson´s disease.
In the last year we developed a new methodology to follow, in parallel, neural
activity and the behaviour of mice with accelerometers.
The role of different striatal circuits
in action learning. Top: Mice
performing a behaviour task–walking
on a rotating rod–which requires
action learning that depends on
striatal circuits in the brain. Bottom:
Identification of striatal medium
spiny neurons of the direct pathway
expressing D1 dopamine receptor
(in red) and striatal medium spiny
neurons of the indirect pathway
expressing D2 receptor (in green).
Note the two populations do not
overlap..
(Catherine French)
20
Inbal Israely
Neuronal Structure & Function
Group members
Ali Argunsah (PhD Student)
Yazmín Ramiro Cortés (Postdoctoral Fellow)
Anna Hobbiss (PhD Student)
Activating single dendritic
spines. A fluorescent reporter
We are interested in understanding how activity can lead to specific is introduced into a subset of
structural changes in neurons that may be important for learning, and how pyramidal neurons in cultured
hippocampal brain slices so that
such changes affect connectivity within neural circuits. We would also individual spines can be visualized.
Using 2-photon microscopy and
like to understand how the structural diversity among neurons contributes photoactivation of caged glutamate,
to connectivity in the brain. The current focus is on single neurons, even the neurotransmitter is released
only at the site of stimulation. This
single spines, to understand the cellular mechanisms that are important allows us to examine how neurons
modify individual synapses at which
for synaptic plasticity and learning. Using 2-photon uncaging of glutamate information is received. We can vary
together with live imaging of neurons, we are able to directly probe the the type of stimulation delivered at a
given input in order to mimic different
structural consequences of activity at single inputs – as seen through forms of activity. Additionally, we can
examine how experience at multiple
changes in the size and shape of spines – as well as through changes in synapses may become integrated,
synaptic weights. Furthermore, by stimulating multiple neuronal inputs, we and what are the mechanisms which
underlie such processing by the
can begin to understand how spines cooperate or compete for the expression neuron.
of plasticity within dendritic domains, and how local protein synthesis plays
a role in these changes. Interestingly, several mental retardation disorders
in humans are characterized by abnormal spine morphology together with
alterations in protein translation. Studying neurons from animal models
of these disorders may elucidate the mechanisms underlying the cognitive
dysfunction, and shed light on the relationship between structure and
function. By combining molecular and genetic tools together with imaging
and electrophysiological methodologies, we investigate how information is
physically stored in the brain.
Dendritic compartmentalization of protein synthesis-dependent synaptic
plasticity
We aim to visualize structural changes that occur in living spines in
response to protein synthesis dependent forms of activity. We will examine
how activity at multiple spines leads to structural changes and changes
in synaptic weights within a dendritic branch.
We found in 2010 that protein synthesis dependent stimulation of spines can
facilitate plasticity at neighbouring spines for up to an hour and over long
distances (70 um), using either cAMP agonists or through dopamine receptor
activity. Spines can also compete for cellular resources if stimulated too
closely together in time, and later stimulated spines can join the competitive
process. These findings demonstrate that the spatial clustering of synapses
provides greater computational power to a neuron.
21
Structural correlates of bidirectional changes in synaptic efficacy
Synaptic potentiation leads to spine enlargement at individual synapses,
and we aim to elucidate the structural consequences of synaptic depression
at single spines. We will determine how bidirectional changes in synaptic
strength correlate with structural modifications at the modified inputs, and
whether these changes depend on new protein synthesis.
In the past year we have induced long lasting synaptic depression
through the activation of metabotropic glutamate receptors (mGluRs) in
hippocampal organotypic slice cultures. We have imaged subsets of spines
from these neurons for up to four hours. Additionally, we have initiated
electrophysiological recordings from these cells in order to monitor the
synaptic responses.
Structural correlates of naturalistic spike trains at single synapses
We aim to mimic naturally occurring patterns of activity with glutamate
uncaging at individual spines, in order to determine the structural and
plasticity correlates of these forms of activity. We will use this information
to model neuronal information processing.
Based on in vivo electrophysiological recordings from hippocampal CA3
neurons, glutamate uncaging protocols will be designed and used to stimulate
individual spines on CA1 cells. We are developing software that will allow greater
precision in the quantification of structural changes. Electrophysiological
recordings in hippocampal organotypic slice cultures are underway in order
to monitor the plasticity induced by the different stimulations.
Adam Kampff
Intelligent Systems
The neural systems that underlie human intelligent behavior have antecedents
in the brains of all animals. The Kampff lab develops conceptual and technical
tools for characterizing the behavioral strategies that brains (primarily those
of rodents) use to learn about and interact with their environments, as well as
new techniques for recording neural activity from behaving animals. These
two goals of the lab are briefly summarized below:
How does the brain construct a model of the world?
Before we can ask “how” brains encode information about their environment,
we must first understand “what” information is encoded. The Kampff lab uses
22
behavioral assays in which the statistics and physics of the environment are
under experimental control (e.g. virtual worlds). By altering environmental
properties and accurately monitoring animal behavior, we use these assays
to determine the environment model that an animal has learned. Currently,
the lab is developing the new tools for behavioral tracking and virtual reality
that will be necessary to implement these systems. The first behavioral
experiments will begin at the CCU in the spring of 2011. Future lesion
studies, neural recordings, and optogenetic manipulations are planned;
these experiments will involve collaborations with researchers throughout
the CF.
Developing high-performance microfabricated devices for recording
neural activity
The Kampff lab has initiated, and will coordinate, a collaboration between
the Center for Materials Research (CENIMAT) of the Universidade Nova de
Lisboa and neuroscientists of the Champalimaud Foundation. CENIMAT
researchers are experts in the design and fabrication of nanoscale
devices; techniques with the potential to fundamentally change the way
neuroscientists record and manipulate activity in the brain. The collaborative
project between CENIMAT and the Kampff lab involves two principle tasks:
the rapid design and microfabrication of neural electrode variants using
advances in nanoscale materials processing, and the evaluation of each new
device’s performance for acute and chronic recordings from mammalian
brains. The fast development-evaluation cycle of new electrode designs
(i.e. devices can be created at CENIMAT and tested at the CCU within the
same day) distinguishes this collaboration from past attempts to bring
advances in nano/micro-scale technology to neuroscience. Our ability
to test numerous variants, directly in the varied model systems that CF
researchers use, promises rapid advances in the performance and scale of
neural recording devices, and will establish the CF as a pioneer for advanced
techniques in neuroscience.
23
Susana Lima
Neuroethology
Group members
Kensaku Nomoto (Postdoctoral Fellow)
Vanessa Urbano (Technician)
Léa Zinck (Postdoctoral Fellow)
We are interested in the brain mechanisms underlying female mate choice,
sexual behaviour and the interaction between the two. As an animal
model, we use wild-derived inbred house mice, which allow us to perform
experiments that address evolutionarily-motivated questions in a controlled
laboratory setting. We are currently investigating how females assess the
quality of prospective mates and what aspects of experience shapes female
choices. We are also actively developing new behavioural paradigms to
measure and manipulate the variables that affect female sexual arousal and
receptivity. To address our goal of understanding how patterns of neural
activity give rise to these processes, we employ approaches ranging from
electrophysiological recordings in behaving animals to genetic manipulation
of neuronal networks.
The hybrid zone between Mus
musculus musculus and Mus
musculus domesticus in Europe.
House mice in Europe are derived
from a common ancester originating
in the Indian subcontinent, which
spread through Europe with
agriculture. Two subspecies have
developed in allopatry: Mus musculus
musculus and Mus musculus
domesticus. Starting 6800 years ago,
these two subspecies established
a contact zone, spanning from
Denmark to the Mediterranean.This
hybrid zone exhibits assymetric mate
choice, which in part has contributed
to the still current separation of
the two subspecies: while musculus
females prefer to mate with
musculus males, domesticus females
mate indiscriminately. We have
developed a behavioural paradigm
in the laboratory using inbred wild
derived animals of the subspecies
musculus (PWD and PWK) and
laboratory strains of mice (Black 6)
as domesticus.
Neuronal mechanisms for mate choice in mice
Our main goal was to develop a behavioural paradigm of mate choice in mice
to then investigate the neuronal mechanisms responsible for representing
mates of different values and how comparison of competing alternatives
are made. We have used a mate choice paradigm inspired by the natural
situation observed in the hybrid zone between Mus musculus musculus and
Mus musculus domesticus in Europe.
In 2010 we have established a mate choice paradigm with M. m. musculus
and M. m. domesticus, where musculus females exhibit a strong and reliable
preference for their own subspecies. We have also established that this
preference is influenced by early imprinting mechanisms and it increases
with multiple testing. Furthermore, the preference for a specific male is
not absolute, but rather flexible and dependent on the alternatives that
are available.
Neuronal mechanisms underlying sex hormone-dependent switching of
sexual receptivity
Female sexual receptivity changes across the reproductive cycle, being
maximal during the fertile phase. This represents an interesting
24
state-dependent behavioural output, where the interaction of sexual hormones and the physiology of neuronal circuits alters the way a female treats
the same male stimulus. We are interested in understanding the role of the
ventromedial nucleus of the hypothalamus (VMH) in the control of this recep- Mus musculus musculus females
(PWK) exhibit a strong and reliable
tivity switch. To this end, we are performing electrophysiological recordings preference for their own subspecies.
PWD females exhibit a strong
of this area in naturally cycling female mice exposed to male stimuli.
During the past year we have developed and troubleshooted electrophysiological recordings in the VMH of naturally cycling, freely moving females.
We are able to record from well-isolated neurons from this area, and we can
observe stimulus triggered responses. We are currently testing other types
homosubspecific preference for PWK
males, resembling what we observe
in the wild. For 54 PWD females
tested, we observed a significant,
reproducible and robust preference
for PWK over B6 males. The overall
PI for PWK is strong and reproducible
across individuals. Paired t-test:***
p<0.001.
of electrodes in order to increase the yield of these experiments.
Female sexual behaviour: neuronal pathways for arousal termination
Like all behaviours, sexual arousal has a beginning and an end. Sensory
genital stimulation received by the female during copulation (sensed by
mechanoreceptors present in the cervix and clitoris) is relayed to the
brain and is important for the rewarding effects of copulation and for its
termination. Despite being a fundamental aspect of sexual behaviour, very
little is known about how the brain integrates the genital stimulation received
during copulation and how the brain uses this information to inhibit further
sexual arousal.
In the past year we have started by establishing a protocol to trace the
genital input to the brain, by using pseudo rabies viruses (PRV) expressing
green fluorescent protein. PRV infects axon terminals of neurons and after
infecting a neuron, jumps to synaptically connected neuronal partners.
By employing this method we are investigating which brain areas are
synaptically connected to the genital organs that receive stimulation during
copulation.
Recordings from isolated neurons
of the ventromedial nucleus of the
hypothalamus (VMH), with stimulus
triggered responses. An example
of a putative hypothalamic neuron
that responded selectively to female
presentations. Spike histogram are
shown (bin width = 1 sec). This
neuron shows selective responses
to the presentations of females
from different strains (red). Colors
indicate the time in which the stimuli
are presented: red, anesthetized
female; blue, anesthetized male;
yellow, a food pellet; green, only
plastic case (control condition); gray,
artifacts. Vertical axis shows firing
rate (number of spikes per second);
horizontal axis shows the time
from the beginning of the session
(in seconds).
Zachary Mainen
Systems Neuroscience
Group members
Niccolò Bonacchi (PhD Student)
Patricia Correia (PhD Student)
Gil Costa (PhD Student)
A custom fiberoptic light detection
system developed in our group,
which we will use to measure
fluorescence changes in freely
moving rats and mice.
Eric Dewitt (Postdoctoral Fellow)
Guillaume Dugué (Postdoctoral Fellow)
Ana Rita Fonseca (PhD Student)
25
Thiago Gouvêa (PhD Student)
Hope Johnson (Postdoctoral Fellow)
Magor Lorincz (Postdoctoral Fellow)
Sara Matias (PhD Student)
André Mendonça (PhD Student)
Masayoshi Murakami (Postdoctoral Fellow)
Maria Inês Vicente (PhD Student)
We are interested in understanding the principles underlying the complex
adaptive behavior of organisms. Starting with quantitative observations of
animal behavior, we aim to integrate quantitative cellular and systems level
experimental analysis of underlying neural mechanisms with theoretical,
ecological and evolutionary contexts. Rats and mice provide flexible
animal models that allow us monitor and manipulate neural circuits using
electrophysiological, optical and molecular techniques. We have made
progress using highly controlled studies of a simple learned odor-cued
decision task and are extending our focus toward more complex behaviors.
Projects in the lab are wide-ranging and continually evolving. Current topics
include (i) olfactory sensory decision-making, (ii) the function of the serotonin
system, (iii) the role of uncertainty in brain function and behavior.
Optogenetic identification and control of serotonin neurons in behaving
animals
Serotonin is an important neurotransmitter implicated in a wide variety
of physiological functions and psychopathologies, but whose function is
not well understood. Critically, very little is known about the activity of
serotonin-releasing neurons in the brain. To address this problem, we are
using optogenetic tools that target this class of cells via specific promoters
to selectively monitor, stimulate and inhibit serotonin neurons. We aim to
test specific hypotheses concerning the role of serotonin in brain function
and behavior.
In the past year, we focused on validating and improving our techniques
for expressing light-gated channel channelrhodopsin-2 (ChR2) in 5-HT
neurons. We tested our custom adeno-associated virus (AAV) in rats and
compared it to a double-floxed inverted ORF (DiO) strategy in the mouse.
With this improved tool in hand, we are now testing the behavioral effects
of stimulating 5-HT neurons.
In parallel, we produced an AAV for specifically expressing the calcium
sensor GCaMP3 in 5-HT neurons and developed a custom fiberoptic light
detection system, which we will use to measure fluorescence changes in
freely moving rats and mice.
26
Olfactory objects and decisions: From psychophysics to neural computation
The overall aim of this line of work is to understand the neural computations
that make olfactory object recognition possible. We hypothesize that complex
odor stimuli are represented using a probabilistic population code and
processed in a Bayesian optimal fashion by the nervous system. To link these
normative ideas to specific neurophysiological and behavioral predictions,
we are formalizing them using computational models. Experimentally,
our primary goal is to monitor and perturb object representations in the Experimental setup of a
rat performing an olfactory
functioning, computing brain. To this end, we deploy psychophysical tasks in categorisation task, which is being
rats, which formalize complex real-world olfactory problems and also allow used to investigate the computation
of decision uncertainty through
us to operationalize cognitive processes such as attention and memory. By inactivation and electrophysiological
combining such quantitative paradigms with large-scale neural ensemble
recordings on the olfactory system.
recordings in the olfactory cortex, we can study how populations of neurons
encode and process complex odor scenes, attempt to account for behavioral
performance, and test the predictions of our theoretical models.
Speed-accuracy tradeoffs (SATs) are well known in decision-making, and can
involve large (>50%) changes in decision time, but are not always observed, as
we have previously shown in an odor mixture categorization task. Why some
tasks benefit from more temporal processing than others is not well understood.
Integration models, which capture a wide range of SAT phenomena, predict that
reaction times (RTs) and performance accuracy are jointly proportional to the
signal to noise ratio of incoming information, assuming the noise fluctuates on
a rapid time scale.
In 2010 we developed a new paradigm involving odor detection. We hypothesized
that fast stimulus noise would dominate the detection task, allowing temporal
integration, while the categorization task would be dominated by slow, trialto-trial variability. We found that SAT was much larger in the odor detection
task than in the mixture categorization task, demonstrating that sensory
integration and the amount of SAT are problem-specific and suggesting that
the locus of performance--limiting noise is a critical variable.
Action selection and action timing in the premotor cortex
Executing the right action at the right moment is important for adaptive
behavior.
Our aims are to understand what features of future actions are represented in
the neuronal firing patterns in motor cortex, and how the interaction between
neurons gives rise to the selection and timing of actions. To achieve this goal,
we are using multiple single-unit recording techniques in behaving rodents. By
correlating the activity of neurons with the animal’s behavior, we are seeking to
understand the internal representation of future actions in the motor cortex.
In 2010, we found 2 types of potential action timing signals in neural activity
27
in the premotor cortex, one transient signal at the onset of waiting and a
second type showing a ramping of activity up to action initiation.
We also have been developing a new task in which we can easily manipulate
the availability of potential action options. We plan to test the hypothesis
that competing representations may underlie action selection by performing
multiple single-unit recordings.
Evaluating the reliability of knowledge: Neural mechanisms of confidence
estimation
Humans and other animals must often make decisions on the basis of imperfect
evidence. How does the brain compute confidence estimates about predictions,
memories and judgments? Previously, we found that a population of neurons in
the orbitofrontal cortex (OFC) tracks the confidence in decision outcomes. We
aim to extend these observations by testing whether confidence-related neural
activity in the OFC is causally related to confidence judgments and by testing
how uncertainty about a stimulus in the course of decision-making may be
represented and computed in olfactory sensory cortex.
We hypothesize that the tubercle, an early olfactory structure that has both
cortical and striatal properties, is a key player in olfactory category decisions
and predict that both confidence and action values are represented and
computed therein. To test this idea, in 2010 we have developed a modified
confidence reporting task that allows us to disambiguate key variables related
to the decision process and are in the process of conducting electrophysiological
recordings from multiple single units in the olfactory tubercle and cortex.
Marta Moita
Behavioural Neuroscience
Group members
Elizabeth Rickenbacker (PhD Student)
Andreia Cruz (PhD Student)
Ana Gregório (Research Technician)
Marta Guimarães (PhD Student)
Ana Pereira (PhD Student)
Scott Rennie (PhD Student)
We are interested in understanding the neural mechanisms underlying
behavioral plasticity using a combination of behavioral, pharmacological,
molecular and electrophysiological tools. We are particularly interested in
Diagram of proposed circuit for
tAFC. When a short trace interval
is used, a projection from the mPFC
to the amygdala is involved. When
a long interval is used, the mPFC is
required to communicate with the
hippocampus, so that this structure
can convey a representation of the
episode, bridging tone and shock, to
the amygdala.
28
studying the neural basis of memory formation. We chose to focus on fear
learning, where animals learn to fear cues that are predictive of aversive
events or threats. Studying fear learning presents several advantages: it is
conserved across species; it entails fast robust learning and very long lasting
memories; its neural circuitry is well described; it may bring insights into the
neural mechanisms underlying anxiety disorders. More recently, we started
studying learning and decision making in the context of social interactions.
Our goal is to bridge the studies on fear learning and social behavior in an
attempt to look at the fear system in all its complexities.
Neural Mechanisms of trace auditory fear conditioning
This project focuses on the role of different memory systems in trace auditory
fear conditioning (tAFC). Our aim is to unravel how the association between
two stimuli separated in time is formed in the brain. Preliminary findings led
us to hypothesize that the strategy used by the rats to learn the association
between tone and shock depends on the length of the trace interval between
the two stimuli. In accordance with these results we found that temporary
inactivation of the hippocampus affects tAFC only when long trace intervals are
used. In contrast, inactivation of either the medial prefrontal cortex (mPFC),
thought to be important for working memory, or the amygdala, important for
fear learning, disrupts learning irrespective of interval length. We have begun
to test the role of mPFC –amygdala and mPFC-hippocampus connections in
the acquisition of tAFC with both short and long trace intervals.
Neural Mechanisms of discriminative auditory fear conditioning
This project aims at elucidating the role of the different auditory input pathways
to the amygdala, a crucial structure for the acquisition of auditory fear
conditioning. To this end we are performing lesions to each of these pathways
and testing their role in the acquisition and expression of discriminative
auditory fear. Previously we had found that both input pathways are necessary
for intact auditory discrimination, in the context of fear learning. Thus,
although either one alone is sufficient for the acquisition of fear of a sound,
neither one can establish normal discrimination between a tone that is followed
by shock and one that is not. Next, we tested the role of the two pathways in the
recall of discriminative fear and found that only the direct thalamic, but not
the cortical, projection to the amygdala was important for normal expression
of discriminative fear. Finally, we found that the same thalamic pathway was
important for the recall of fear extinction, suggesting a role of this pathway in
the suppression of fear of neutral or safe auditory stimuli.
Cooperation in social dilemmas in rats
Game theory has constituted a powerful tool in the study of the mechanisms
of reciprocity. Having shown, in a Prisoner’s Dilemma game, that rats shape
29
their behaviour according to the opponent’s strategy and the relative size
of the payoff resulting from cooperative or defective moves, we now aim at
dissecting the mechanisms underlying the decision-making process during
such social dilemma games. We have designed and set-up an automated
maze to study the behavior of rats in different social dilemma games, such
as the Stag Hunt and the Snow drift game, which allow for dissection of the
factors that govern cooperation between two rats.
Mechanism of vicarious fear
This project aims at investigating the mechanisms underlying vicarious fear
in rats. It has been shown that rats can learn from social interactions, however
the mechanisms underlying this form of learning are poorly understood.
In this project we are focusing on social transmission of fear. In collaboration
with Dr. Christian Keysers, we have developed a paradigm for studying
vicarious fear in rats. We have found that a rat will show vicarious fear
when observing a conspecific being shocked, provided that it has had prior
experience with shock. This finding suggests that vicarious freezing in rats
is empathic in nature. Furthermore, we found that the rat being shocked will
freeze more in the presence of an experienced observer than in the presence
of a naïve one and that the amount of freezing is correlated with the number
of alarm calls emitted by the two rats.
Michael Orger
Vision to Action
Group members
Claudia Feierstein (Postdoctoral Fellow)
João Marques (PhD Student)
Our brains process and integrate sensory information,
experience, and internal states to plan and execute
appropriate behavioural responses. Understanding how
these processes are implemented in neural circuits is
a major goal of contemporary science. We address this
question using visuomotor responses in zebrafish, whose
brain has the same basic vertebrate organization as ours,
but is numerically about a million times less complicated.
Small and transparent, zebrafish are uniquely well suited
to take advantage of recent advances in optical and genetic
methods for exploring neural function.
Figure 2 – Structure and function of neural circuits in the
zebrafish
a) Projection of two photon image stack of motor control
neurons in the zebrafish brainstem. b) Optical section of
panneural GCaMP fish with superimposed color map of
direction preference recorded by functional imaging (see
inset look up table). c-d) Stable GFP expression driven in
specific neurons in the mid/hindbrain using conserved
zebrafish enhancer sequences
30
Characterization of sensorimotor transformations
To know how a circuit works, we need to know what it was meant to do.
We study how the zebrafish brain transforms vision into action, by recording
with high-speed cameras the behaviour of fish swimming freely in virtual
reality environments where we can precisely control visual stimulus
presentation and sensory feedback. Zebrafish show an array of robust and
complex visual responses even in the first days of life: they escape looming
predators, hunt down and eat moving prey, chase smaller fish away from
food and use eye and body movements to compensate for their motion relative
to the world. We aim to develop quantitative descriptions of each of these
behaviours, using simple artificial stimuli, and study how the brain integrates
information from multiple cues to drive appropriate motor responses.
Whole brain functional imaging
Behaviour depends on dynamic activity in neural circuits that span multiple
areas throughout the brain. A key advantage provided by the small,
transparent brain of the zebrafish is the ability to image non-invasively, in
vivo, activity in all neurons in an unbiased manner. We use a custom two
photon microscope to image fish expressing genetically encoded calcium
indicators throughout the brain, while they respond to visual stimuli, to build
functional maps of a vertebrate brain with single cell resolution. We have a
particular interest in determining how the precise control of movements
exhibited during visually guided swimming activity is executed by projection
neurons in the brainstem motor control system, a small neural population,
many of which can be uniquely identified from fish to fish (see Figure).
Targeted Perturbations
While it is useful to correlate the activity of neurons with behaviour, we
also need to establish a causal link between the two. This has historically
been much more difficult, because 1) we have lacked ways to non-invasively
and reversibly manipulate neural activity, and 2) the number of possible
manipulations is intractably large. The development of sensitive, light-gated
ion channels to up- and down-regulate activity has recently provided a
powerful solution to the first problem. The second issue is dealt with by having
a comprehensive functional map of the brain to build strong prior hypotheses
about what neurons are doing. We are developing tools to express transgenes
in targeted neuronal populations with spatial and temporal specificity.
We will use these tools to manipulate spiking in identified neurons within
circuits to reveal how activity in individual cells contributes to behaviour
of the whole organism.
31
Joseph Paton
Dopamine in Action Learning
Group members
Rui Azevedo (PhD student)
Gustavo Mello (Technician)
Sofia Soares (MSc student)
The film director Elia Kazan once said that directing is “turning psychology
into behavior”. Your brain is charged with the same task every moment Neurophysiology of time encoding
in the rodent striatum. A - Scheme
you are awake. Aside from reflexes, actions are almost always, at least of the Serial Fixed Interval (SFI)
initially, directed in nature. Disease states such as Parkinson’s disease, lever pressing task. Rats and mice
adjust pressing times in response
where voluntary action is inhibited, and obsessive compulsive disorder to different fixed intervals (FI) of
reinforcement. We analyze behavioral
and drug addiction, where actions cannot be terminated, highlight the measures that co-vary with the time
importance of proper direction of action for normal functioning. The core duration being sampled, such as the
time of the first lever press after
of my laboratory’s research is to advance our understanding of the neural collecting a reward, that we refer to
as “post reinforcement pause”. Here
mechanisms by which the actions that make up adaptive behavior are learned (B - left) we calculated the median
and generated. Taking a cue from Mr. Kazan, we begin by developing well- post reinforcement pause within
blocks of trials of the same FI in a
-controlled behavioral tasks for the investigation of signals related to temporal single session and on the right (B
- right) we show the density function
processing in the brain of awake-behaving rodent model systems. Currently, of the pressing start times. We can
we are particularly interested in understanding how the neurotransmitter see that rats vary their pressing
start times in relation to the FI of
dopamine (DA) modulates neural functioning within the basal ganglia, an reinforcement.
evolutionarily aged collection of structures historically thought of as being
important for movement. In particular DA appears important for normal
timing of behavioral responses. Thus, we have developed simple cognitive
tasks in rodents in which animals must learn to time intervals. Our approach
employs multi-site neurophysiological recordings, as well as theoretical,
pharmacological, and molecular biological techniques.
Neurophysiology of time encoding in the rodent striatum
We aim to identify neural correlates of time intervals that rats estimate
during performance of a novel timing task.
In the past year, we continued this project by recording the spiking activity
from single neurons while rats to press a lever in order to gain rewards at
defined intervals, classically called operant conditioning on a Fixed Interval
(FI) reinforcement schedule. We have adapted the classical FI schedule
in such a way that we can observe a behavioural readout that reflects the
animals’ changing knowledge about time until reward. We have recorded
from hundreds of neurons in the striatum, a major input area of the Basal
Ganglia that has been implicated in timing. We find that the dynamics of
neuronal activity across a population of neurons can be used to encode time
32
over the range of tens of seconds to a minute. We developed decoding schemes
to read out time relative to our task events on a moment by moment basis,
and found that this moment by moment estimate covaried with a quantitative
description of animals’ estimates of time until reward. These results should
have far-reaching impact on our understanding of time encoding in the brain,
as well as the field of associative and reinforcement learning. In addition
this work provides a launching point for deeper investigation of the neural
mechanisms of time encoding that we are developing in mice, where we have
access to more molecular biological and genetic tools.
Optogenetic manipulation of Dopamine during timing behavior
We plan to test the hypothesis that manipulation of Dopamine through
physiolo-gically realistic means alters timing performance and neural
signals in the Striatum. In addition we plan to determine the genetic identity
of neurons during neurophysiology experiments to build more informed
circuit models for how the Basal Ganglia functions during timing behavior.
In the past year, we have continued a parallel set of timing studies in mice
in order to take advantage of the increased molecular power of the mouse
relative to the rat. We have trained mice on a classic temporal reproduction
task, called the peak interval task, and the SFI task mentioned above. By
combining viruses dependent on CRE recombinase activity for expression of
transgenes, with mouse lines expressing CRE in specific basal ganglia cell
types, we plan to express light sensitive channels and pumps in targeted
locations within the basal ganglia circuit. Stimulating these proteins with
light during experiments will provide us with two potentially powerful pieces
of data. First, we will be able to ask what type of cell we are recording from
in vivo much more easily and in higher volume than was available with older
techniques. Second, we can test hypotheses about the role of activity in
specific populations of neurons for timing behavior.
Optogenetic identification of striatal
cell-type during timing behavior.
We are working on selective viralmediated ChR2 expression in striatal
cell types. A – A fluorescent image
from a coronal section of a D2-Cre
mouse brain (left) compared to a
coronal mouse brain schematic
(right) shows striatal D2 medium
spiny neurons (MSNs) expressing
ChR2– YFP following injection of
Cre-dependent AAV into D2-Cre BAC
transgenic mice. CPu – Caudateputamen (striatum). B – Confocal
image of ChR2–YFP-expressing
neurons in the striatum (Arrow). C
– Confocal image of To-Pro-3 staining
in the same region as in panel B. D
– Panels B and C merged. The white
box indicates the region shown in
panel E. E – Example of a spiny
dendrite from a D2MSN expressing
ChR2-YFP. Scale bars = (B, C and D)
15μm: (E) 5μm.
33
Carlos Ribeiro
Behavior and Metabolism
Group members
Célia Modesto Baltazar (Research Assistant)
Laura Napal Belmonte (Postdoctoral Fellow)
Ana Carolina Doran (Research Assistant)
Ana Paula Elias (Lab Manager and Research Assistant)
Samantha Herbert (PhD Student)
Teresa Montez (Postdoctoral Fellow)
We are interested in understanding how molecular and cellular mechanisms
control complex biological processes at the level of the whole organism.
For this we are focusing on how the internal metabolic state of the fruit fly
Drosophila melanogaster affects its behavioural decisions. Starting from
novel behavioural paradigms we use molecular genetic techniques to identify
and characterize genes and neuronal populations involved in producing the
appropriate behavioural response to a specific metabolic need of the fly.
Molecular mechanisms of nutrient choice
We want to understand how Drosophila knows what type of nutrients it needs
and which are the molecular mechanisms used by the nervous system to Top What type of food should the
animal choose?
change the behaviour of the animal to allow it to find and eat the required Middle Drosophila adult brain (gold)
with specific neuronal subsets
nutrients.
Last year we showed that mating status is a critical modulator of nutritional
marked by GFP (green).
Bottom Automatically tracked path of
a foraging fly
decision-making in females, and that it relies on the action of the sex peptide
receptor (SPR) in ppk+ sensory neurons. Neuronal TOR/S6K function is
another critical input to this decision, possibly signaling the fly’s current
nutritional status. We are now looking into how this conserved pathway acts
in the nervous system to control feeding. Furthermore we have continued to
analyze genes identified as being required for nutrient choice in a neuronal
whole-genome RNAi screen. Taken together these studies will provide a
model and an entry point for studying nutrient balancing and value-based
decision making at the molecular level.
Neuronal mechanisms of nutrient choice
We want to identify and analyze the neuronal networks used by Drosophila
to change the behaviour of the animal to allow it to find and eat the required
nutrients.
In the past year we have used genetic approaches to identify neuronal
populations which are required for nutrient choices. Currently we are
34
analyzing the identified neuronal substrates for nutrient homeostasis to
understand how these neuronal populations act to guide feeding decisions.
Quantitative analysis of feeding behavior in Drosophila
In collaboration with the laboratory of Aldo Faisal at Imperial College London
we have developed a prototype setup which will allow us to use automated
video analysis to quantitatively link genetics to feeding behaviour in the fruit
fly, the main aim of this project.
Maria Luísa Vasconcelos
Instituto Gulbenkian de Ciência
Innate Behaviour
Group members
João Afonso (Research technician)
Sophie Dias (Research technician)
Dennis Hermann (PhD student)
Nuno Martins (Masters Student)
Ricardo Neto (Postdoctoral Fellow)
Nélia Varela (Postdoctoral Fellow)
Animals exhibit behavioural repertoires that are often innate and result
in stereotyped sexual and social responses to their environment. Innate
V Glomerulus Photoactivation
The figure shows the two antennal
lobes (ALs) of a Drosophila
melanogaster. The V glomerulus has
been photoactivated in the left AL and
it is brighter than the V glomerulus in
the right AL (arrowheads). The cell
bodies that are connected to the left
V glomerulus also became brighter
after its photoactivation (arrows).
behaviours do not require learning or experience and are likely to reflect the
activation of developmentally programmed neural circuits. We are interested
in the nature of defined neural circuits: how activation of circuits elicits
specific behaviours. In complex organisms it has been extremely difficult
to study a circuit beyond the early stages of sensory processing. Drosophila
melanogaster is an attractive model system to understand a circuit because
flies exhibit complex behaviours that are controlled by a nervous system
that is numerically five orders of magnitude simpler than that of vertebrates.
We use a combined behavioural, genetic, imaging and electrophysiological
approach to determine how defined neural circuits and their activation elicit
specific behaviours.
Female receptivity
Genetic studies have elucidated how Drosophila male courtship behavior
is specified and its circuit components are being dissected at a surprising
speed. The circuit of female behavior on the other hand has been largely
uncharacterized. We use a behavioral protocol that allows us to selectively
35
inactivate subsets of neurons in the adult flies only. We use this behavioral approach and combine it with anatomical and functional dissection
of the circuit.
In 2010 we have focused our research on the neurons that express apterous.
Inactivation of apterous expressing neurons leads to a marked reduction of
receptivity of the female to the male’s courtship efforts. It is unlikely that all
neurons that express apterous are involved in female receptivity. We have
begun running experiments that allow us to zoom in on the apterous neurons
that affect the behaviour of the female.
Across species stress odor response
Stressed Drosophila melanogaster release an aversive odorant that elicits
a robust avoidance response in test flies. Our data indicate that stress odor
avoidance is not common to all Drosophilids. This behavioral difference
between melanogaster and some of its sister-species provides a powerful
framework, amenable to genetic, developmental and anatomical dissection,
to investigate how evolution has shaped distinct responses to an environ- T Maze
mental cue.
In the past year, we have characterised the response of four Drosophilids to
CO2, the only identified active component of the Stress Odor. With this purpose
we built a T-maze with odor flow to test flies to controlled concentrations of
CO2. We found that the responses vary across the tested species. We began
characterizing the response of additional Drosophilids in order to understand
the full range of variation so that in the future we can find the anatomical
and genetic basis of the variation.
We have also established a photoactivation protocol that allows visualising
all the neurons that innervate the V glomerulus that responds to CO2.
We see the same number of cell bodies activated within different brains.
Photoactivation is done in live brains so we can in the future characterise
the electrophysiological response of all the neurons that innervate the V
glomerulus.
36
ASSOCIATED RESEARCH GROUPS
Domingos Henrique
Instituto Medicina Molecular (IMM)
& Instituto Gulbenkian de Ciência (IGC)
Neural Development
Group members
Elsa Abranches (Postdoctoral Fellow)
Evguenia Bekman (Postdoctoral Fellow)
Aida Costa (PhD Student)
Ana Margarida Cristóvão (Research Technician)
Cláudia Gaspar (Postdoctoral Fellow)
Sara Ferreira (Research Technician)
Catarina Ramos (Postdoctoral Fellow)
Filipe Vilas-Boas (PhD Student)
Our main interest is to understand the molecular mechanisms that regulate
the genesis of neurons in vertebrate embryos. We believe that a better
knowledge of these mechanisms is a pre-requisite for the development of
cellular replacement therapies to treat neurodegenerative diseases, with a
significant impact on human health. Our research focus on the molecular
events that control the generation of neural stem cells in the embryo, how
these cells are maintained, and how they give rise to the multitude of neurons
that compose the adult CNS. We are using cellular and genetic approaches
to dissect the genetic circuitry that regulates the production of neurons
during embryonic development and have characterized in great detail the
molecular roadmap from embryonic stem cells to differentiating neurons.
Current projects are aimed at investigating the assembly and function
of the corticostriatal circuitry involved in motor control.
Development and function of striatal organization
The striatum is the main input structure from the cortex to the basal ganglia,
and a central component of the corticobasal ganglia circuitry that is involved
in multiple neurological functions like motor learning and motor control,
decision-making, and cognition. The importance of the striatum is reflected
in a number of neurological disorders, including Parkinson’s and Huntington’s
diseases, in which defective neurotransmission or neurodegeneration are
associated with the striatal system.
The current model for the functional organization of the corticostriatal
circuitry is based on the “direct” and “indirect” pathways of the flow of
cortical information through the basal ganglia. The two pathways have
37
opposite influences in the output of the circuitry, with the direct pathway
releasing and the indirect pathway inhibiting movement. Our first aim is to
establish a precise molecular neuroanatomical map of this corticostriatal
circuitry, using state-of-the-art mouse transgenic technology to generate
and analyse a battery of transgenic mice carrying different reporter genes
under control of cell-specific promoters. This shall allow us to identify at the
molecular level the various cellular components of the corticostriatal circuitry
and their spatial organization. This work is in progress and BAC technology
is being used to build the necessary vectors for transgenic production.
Using these tools, we shall next evaluate the functional contribution of the
various identified circuitry components to the establishment of well-defined
behavioral corticostriatal outputs, like initiation of voluntary movement,
skill learning and habit formation.
Rui F. Oliveira
Instituto Superiorde Psicologia Aplicada (ISPA)
& Instituto Gulbenkian de Ciência (IGC)
Animal Behaviour
Group members
At IGC:
Rodrigo Abreu (PhD Student)
Ana Catarina Oliveira (Research technician / molecular biology)
Joana Ferreira da Silva (M.Sc. Student)
Miguel Simões (PhD Student)
Magda Teles (PhD Student)
The main research aim of our group is the understanding of the interrelationship between neuroendocrine mechanisms and social behaviour,
using an integrative approach (i.e. by integrating ecological/evolutionary
analysis with physiological analysis of behavior). With our studies we hope
to contribute to the understanding of how complex social environmental
processes interact with biological systems. I have been developing two main
research lines: (1) to understand how the social environment modulates
hormones and gene expression in order to affect the expression of subsequent
behaviors; and (2) the study of the neuroendocrine mechanisms underlying
behavioral plasticity. Both research lines have been mainly focused in
teleost fish as study models (tilapia, pecock blenny and zebrafish) but I have
also expanded my research to other vertebrate groups, including humans.
In these research lines we combine neuroendocrinology and molecular
biology techniques with behavioural observations and we conduct studies
both in the lab and in free-living subjects.
38
PLATFORMS AND SERVICES
Histology Platform
Coordinator
Susana Lima
Staff
Maurícia Vinhas (Research Technician)
Ana Santos (Research Technician)
The Histology Unit provides a wide range of services related to tissue
preparation to the neuroscience researchers. These include collection, Rat coronal brain section
somatosensory cortex.
fixation, processing, embedding, sectioning and staining of animal tissue Neurons in layers 3 and 5 were
samples. The unit also provides microscopy assistance as well as training to labeled by injecting a retrograde
new users in sample preparation and sectioning. Specific services include:
•Chemical and cold fixation of animal tissue
traveling virus into the contralateral
cortex. Brain slices were processed
by immunohistochemistry methods to
reveal the labeled neurons.
•Processing of fixed tissue for light microscopy
•Embedding (paraffin, etc)
•Cryostat, vibratome and microtome sectioning
•Histochemistry, immunohistochemistry and immunofluorescence staining
of tissue
•Microscopy (fluorescence, bright field and confocal)
Scientific Computing Platform
Coordinator
Zachary Mainen
Staff
Paula Santos (Systems Administrator)
Jörg Löhken (Programmer)
Eric DeWitt (Advisor)
The Information Technology Unit (IT) manages the computer infrastructure
of the neurosciences group, maintaining dedicated web and data backup
servers and provides collaboration and communication tools for the program.
In 2010 we migrated our Google Applications office tools package to the
domain neuro.fchampalimaud.org. We also applied, for and were approved
for, Google Apps for Education which extends the number of users available
to us and provides additional education services in addition to Google email,
mailing lists, web sites, calendars and collaborative documents. IT has also
provided support to the International Neuroscience Doctoral Programme
website and application process. We maintained the CNP internal wiki for
39
information sharing and the external website. In 2010 all web-based services
previously hosted onsite have been migrated to Amazon Web Services, which
provides robust, virtualized servers. We also added a web-based help desk
request tracking application to handle the needs of the IT platform, the new
scientific platforms and move related requests.
Finally, a significant amount of effort in the second half of 2010 was devoted
to planning and preparing for the migration of the CNP IT infrastructure to
its new location and to accommodate the changing services and additional
demands that will be created during that process.
Gene Expression Platform
Coordinator
Susana Lima
Staff
Tatiana Vassilevskaia (Virus Production)
The Gene Expression unit was established in 2009 with the purpose of
developing and producing genetic tools to manipulate the activity of neural
circuits and making them more accessible to research teams. Ultimately,
the goal is to offer the community a collection of different options in terms of
delivery system (viral, electroporation, etc), expression pattern and specificity
(for example, different cell type specific promoters) and expressible genes
(light gated channels, RNA interference, etc).
Recombinant adeno-associated viruses (rAAV) are an effective method of
delivering genes to the mammalian neurvous system and have been the
initial focus of the unit since its establishment in April. Several batches of
rAAVs have been produced at mini-scale and successfully tested in vitro and
two medium scale productions are being currently tested in vivo studies.
Administrative Support Services
Coordinator
Zachary Mainen
Staff
Teresa Carona (Projects manager)
Raquel Gonçalves (Programme Administrator)
Alexandra Piedade (Meetings and Courses Administrator)
Deborah Rocha (Projects Coordinator)
40
The Administrative Support unit (AS) manages all clerical procedures
such as records keeping, budgets and accounting, form design, report
preparation, and website information maintenance, among others. The
many basic informational requests received daily, from both internal
and external sources, are handled in person, by phone, and by email. As
English is the official language of the programme, members have very good
working knowledge of it, as well as Portuguese.
Visit schedules, transportation, and lodging for guests, including speakers and
lecturers, who are so essential to the CNP programme are organized by AS.
For people joining the CNP from outside Portugal, AS facilitates relocation.
Current faculty, laboratory staff, and students receive ongoing support from
AS ensuring that the day to day needs of conducting research are met.
In addition to daily activities, the AS facilitates large annual projects such
as INDP student recruitment, CNP group leader recruitment, and several
scientific workshops.
RESEARCH FUNDING
Fundação Bial
Portugal
•Bial Science Research Grant
Neuronal mechanisms underlying sex hormone-dependent switching of
sexual receptivity
2009-2010
Awarded to Susana Lima
Action selection and action timing in the premotor cortex
2009-2010
Awarded to Masayoshi Murakami
•Bial Research Bursary Grant
Investigating the function of synaptic competition in memory formation
and mental retardation
2011-2014*
Awarded to Inbal Israelly
Elucidating the molecular mechanisms mediating feeding behavior
2011-2013*
Awarded to Carlos Ribeiro
41
Fundação para a Ciência e a Tecnologia (FCT)
Portugal
•Research Project Grant
Dissecção das bases moleculares e dos circuitos envolvidos na intenção
2011-2014*
Awarded to Rui Costa
Unraveling the Neuronal Circuits Underlying Female Receptivity
2010-2012
Awarded to Maria Luisa Vasconcelos
From genes to behaviour: dissecting the basis for CO2 response across
Drosophilids
2010-2012
Neuroendocrine mechanisms of reproductive polyphenisms in the blenny
Salaria pavo
2008-2011
Awarded to David Gonçalves
Alternative reproductive tactics in teleost fish: the peacock blenny (Salaria
pavo) as a study model
2008-2011
Awarded to Rui F Oliveira
Neuroendocrine control of reproductive behavior in the Mozambique tilapia:
mechanisms and effects of the social environment
2008-2011
Stem cell based therapy for inner ear hair cell regeneration
2007-2010
Awarded to Domingos Henrique
42
Notch
signaling
and
regulatory
mechanisms
during
mammalian
neurogenesis
2007-2010
Neural Talk - Scaffold-driven stem-cell regenerative therapy for the spinal
cord injury. Biomimeting neurogenesis in the Central Nervous System
Joint Project with Instituto Nacional de Engenharia Biomédica (INEB),
Porto (Project Leader -Ana Paula Pêgo)
2007-2010
Neural Mechanisms of trace auditory fear conditioning
2007-2010
Awarded to Marta Moita
Winners and losers: social modulation of hormones, brain and behaviour
2007-2010
Effects of social competition and social context on hormones and behaviour:
testing the challenge hypothesis in humans
2007-2010
•Research Associate Fellowship
2008-2013
Awarded to David Gonçalves
•Postdoctoral Fellowship
2010-2013
Awarded to Hope Johnson
2010-2013
Awarded to Teresa Montez
2009-2012
Awarded to John Burkhardt
43
2009-2012
Awarded to Masayoshi Murakami
2008-2012
Awarded to Cristina Afonso
2008-2011
Awarded to Marta Soares
2007-2010
Awarded to Silvia Costa
•PhD Fellowship
2009-2013
Awarded to Ana Rita Fonseca
•PhD Fellowship
2009-2013
Awarded to Dennis Hermann
•PhD Fellowship
2009-2013
Awarded to André Mendonça
•PhD Fellowship
2009-2013
Awarded to Ana Pereira
•PhD Fellowship
2009-2013
Awarded to Scott Rennie
•PhD Fellowship
2009-2013
Awarded to Fernando Santos
•PhD Fellowship
2009-2013
Awarded to Mafalda Vicente
44
•PhD Fellowship
2008-2012
Awarded to Maria Inês Vicente
•PhD Fellowship
2008-2012
Awarded to Magda Teles
•PhD Fellowship
2008-2012
Awarded to Olinda Almeida
•PhD Fellowship
2008-2012
Awarded to Pedro Ferreira
•PhD Fellowship
2008-2012
Awarded to Miguel Simões
•PhD Fellowship
2007-2011
Awarded to Gil Costa
•PhD Fellowship
2006-2010
Awarded to Marta Guimarais
* Awarded in 2010
European Commission
European Union
•ERC Advanced Grant, European Research Council
Optogenetic Analysis of Serotonin Function in the Mammalian Brain
2010-2015
Awarded to Zachary Mainen
•ERC Starting Grant, European Research Council
Neural mechanisms of action learning and action selection: from intent to
habit
2009-2014
45
•Marie Curie International Reintegration Grant
Neural mechanisms of action learning in mouse models
2009-2013
•Marie Curie International Reintegration Grant
Neural mechanisms underlying mate preference and selection in mice
2009-2013
Awarded to Susana Lima
•European Union Grant
Female receptivity
2009-2013
•European Commission, Food, Agriculture and Fisheries, and Biotechnology.
Project: Copewell
A new integrative framework for the study of fish welfare based on the
concepts of allostasis, appraisal and coping styles
2011-2015*
Awarded to Rui Oliveira
•Marie Curie Intra-European Fellowship for Career Development
2010-2012
Awarded to Magor Lorincz
2009-2011
Awarded to Léa Zinck
2008-2010
Awarded to Guillaume Dugué
* Awarded in 2010
International Human Frontier Science Program
Organization (HFSPO)
International
•Human Frontier Science Program
Olfactory objects and decisions: From psychophysics to neural computation
2010-2013
Awarded to Zachary Mainen, Alex Pouget and Matthieu Luis.
46
Oeiras City Council
Portugal
“Começar em Oeiras”- Oeiras Municipality
Neural Circuits of Innate Behavior
2009
PUBLICATIONS
•Carey MR, Regehr WG
Phosphatase activity controls the ups and downs of cerebellar learning
Neuron 67:525-6
•Jin X, Costa RM
Start/stop signals emerge in nigrostriatal circuits during sequence
learning
Nature;466(7305):457-62
•Koralek AC, Long JD, Costa RM, Carmena JM
Corticostriatal dynamics during learning and performance of a neuroprosthetic task
Conf Proc IEEE Eng Med Biol Soc.;1:2682-5
•Derusso AL, Fan D, Gupta J, Shelest O, Costa RM, Yin HH
Instrumental uncertainty as a determinant of behavior under interval
schedules of reinforcement
Front Integr Neurosci. 28;4. pii: 17
•Venkatraman S, Jin X, Costa RM, Carmena JM
Investigating neural correlates of behavior in freely behaving rodents
using inertial sensors
J. Neurophysiol.104(1):569-75
•Yin HH, Costa RM
Striatal dopamine and glutamate in action: the generation and modification
of adaptive behavior. in Frontiers in Neuroscience, The Role of Dopamine
in the Basal Ganglia, ed. Susan Jones
Taylor & Francis Group, Boca Raton, FL, US
•Govindarajan A*, Israely I*, Huang SY, Tonegawa S
The dendritic branch is the preferred integrative unit for protein synthesisdependent LTP
Neuron, 69:132-146 (Paper was in press in 2010)
47
•Feierstein CE, Mainen ZF
Listening to the crowd: neuronal ensembles rule.
Neuron 66(3):334-6
•Ribeiro C, Dickson BJ
Sex Peptide Receptor and Neuronal TOR/S6K Signaling Modulate Nutrient
Balancing in Drosophila
Current Biology, 20(11), 1000-1005
•Ruta V, Datta SR, Vasconcelos ML, Freeland J, Looger LL, Axel R
A dimorphic pheromone circuit in Drosophila from sensory input to
descending output
Nature 468(7324):686-90
•Gonçalves DM, Saraiva JL, Teles M, Teodósio R, Canário AVM, Oliveira RF
Brain aromatase mRNA expression in two populations of the peacock
blenny Salaria pavo with divergent mating systems
Hormones and Behavior 57, 155-161
•Saraiva JL, Gonçalves DM, Oliveira RF
Environmental modulation of androgen levels and secondary sex characters
in two populations of the peacock blenny Salaria pavo
Hormones and Behavior 57, 192-197
•Soares MC, Bshary R, Fusani L, Goymann W, Hau M, Hirschenhauser K,
Oliveira RF
Hormonal mechanisms of cooperative behaviour
Philosophical Transactions of the Royal Society 365, 2737-2750
•Gonçalves DM, Oliveira RF
Hormones and sexual behavior of teleost fishes
In: Norris D.O. (Ed.), Hormones and Reproduction in Vertebrates Volume 1
– Fishes, pp. 119-147. Elsevier, New York, NY
•Soares MC, Côté IM, Cardoso SC, Oliveira RF, Bshary R
Caribbean cleaning gobies prefer client ectoparasites over mucus
Ethology 116, 1244–1248
•Lacava RV, Brasileiro L, Maia R, Oliveira RF, Macedo RH
environment affects testosterone level in captive male blue-black grassquits
Hormones and Behavior, in press (doi:10.1016/j.yhbeh.2010.10.003)
•Ros AFH, Lusa J, Meyer M, Soares MC, Oliveira RF, Brossard M, Bshary R
Does access to the bluestreak cleaner wrasse Labroides dimidiatus affect
indicators of stress and health in resident reef fishes in the Red Sea?
Hormones and Behavior, in press (doi:10.1016/j.yhbeh.2010.11.006)
48
•Galhardo L, Vital J, Oliveira RF
The role of predictability in the stress response of a cichlid fish
Physiology and Behavior, in press (doi:10.1016/j.physbeh.2010.11.035)
•Galhardo L, Almeida O, Oliveira RF
Measuring motivation in a cichlid fish: an adaptation of the push-door
paradigm
Applied Animal Behaviour Science, in press (doi:10.1016/j.applanim.
2010.12.008)
•Costa SS, Andrade R, Carneiro LA, Gonçalves EJ, Kotrschal K, Oliveira RF
Sex differences in the dorso-lateral telencephalon correlate with home
range size in blenniid fish
Brain Behavior and Evolution in press (doi: 10.1159/000323668)
•Antunes R, Moita MA
Discriminative auditory fear learning requires both tuned and nontuned
auditory pathways to the amygdale
J Neurosci. 2010 Jul 21;30(29):9782-7
•Viana DS, Gordo I, Sucena E, Moita MA
Cognitive and motivational requirements for the emergence of cooperation
in a rat social game
PLoS One. 2010 Jan 13;5(1):e8483
* Authors contributed equally
MEETINGS, COURSES, SEMINARS
Meetings Organized
•Imaging Structure and Function in the Zebrafish Brain
European Zebrafish Symposium
CS Vintage Hotel, Lisboa, Portugal
December 2010
Co-Organizer: Michael Orger
49
Invited Seminars and Presentations
at International Meetings
Rui Costa
•Conference “Reward and Decision Making in the Brain”
Jerusalem, Israel.
February 2010
•Winter Plasticity Meeting,
Aruba
February 2010
•1st Sao Paulo School of Translational Science
AC Camargo Hospital, São Paulo, Brazil
April 2010
•University of Maryland Medical School
Baltimore, MD, USA
April 2010
•Institute du Fer à Moulin, Paris, France
May 2010
•Neuroethics Conference
Fundação Calouste Gulbenkian and French Embassy, Lisbon, Portugal
May 2010
•Porto Ciência
Porto, Portugal
June 2010
•EMCCS Summer School
Venice, Italy
October 2010
Magor Lorincz
•Temporal framing of thalamic relay-mode firing by phasic inhibition
during the alpha rhythm
FENS, Amsterdam, Netherlands
July 2010
50
Zachary Mainen
•Neural codes and computations underlying odor-guided decisions
in the rat
Brain Circuits Workshop
Ein Gedi, Israel
February 2010
in the rat
Weizmann Institute
Rechovot, Israel
February 2010
•Targeting the 5-HT system using optogenetics: Towards a post-pharmacological view
Cosyne Workshops
Snowbird, Utah, USA
March 2010
•Neural mechanisms underlying odor-guided decisions in the rat
Cosyne Workshops
Snowbird, Utah, USA
March 2010
in the rat: Uncertainty in brain and behavior
Tamagawa-Caltech Lecture Course on Decision-Making
Tamagawa University, Tokyo, Japan
March 2010
•Toward a Translational Science of Mental Illness: A Perspective on 5HT from Systems Neuroscience
1st Sao Paulo School of Translational Science
April 2010
•Translational Science of Mental Illness Two Perspectives from Systems
Neuroscience
1st Sao Paulo School of Translational Science
April 2010
51
•Neural mechanisms underlying odor-guided decisions
Form and Function of the Olfactory System Workhop,
Janelia Farm, Ashburn, USA
May 2010
•Neural mechanisms for decision making in the rat Variability &
uncertainty in brain and behavior
Oxford University
Oxford, UK
June 2010
•Reading out neural circuits for decision-making in the rat
Rochester CVS Symposium
Photons and Neurons, University of Rochester
Rochester, NY
June 2010
•Odor-guided decisions: Behavior and sensory representations
Computational and Cognitive Neuroscience Course, CSH Asia
Suzhou, China
July 2010
•Neural mechanisms for rapid perceptual decisions
EMBO|EMBL Symposium: Structure and Function of Neural Circuits
Heidelberg, Germany
September 2010
•Neural mechanisms for olfactory decision-making
Instituto de Neurociencias
Alicante, Spain
December 2010
•Neural mechanisms for decision making in the rat Uncertainty in
brain and behavior
Adrian Seminar, University of Cambridge
Cambridge, UK
December 2010
Masayoshi Murakami
•Neural substrates of impulsive decision making and its withholding
Workshop on the Computational Properties of the Prefrontal Cortex
Whistler, BC, Canada
September 2010
52
Joseph Paton
•Time and learning in the rodent striatum
Batsheva Symposium on Reward and Decision-making in the Brain.
Jerusalem, Isreal
February 2010
Carlos Ribeiro
•The Molecular and Neuronal Control of Nutrient Choice in Drosophila
1st Nutritional Homeostasis Workshop
Bonn, Germany
May 2010
•Nutricional Value-Based Decisions in Drosophila
Department of Bioengineering Imperial College London
London, UK
August 2010
University College London
London, UK
August 2010
ESF-EMBO conference on “Functional Neurobiology in Minibrains: From
flies to robots, and back again.”
Sant Feliu de Guixols, Spain
October 2010
•Drosophila, a model to study neuronal nutrient sensing pathways
and how they control feeding behaviour
14th Portuguese Obesity Conference,
Porto, Portugal
November 2010
14th Portuguese Obesity Conference,
Porto, Portugal
November 2010
53
Nélia Varela
•Characterizing the CO2 neuronal circuit: the initial steps
Drostuga
Lisbon, Portugal
December 2010
GRADUATE TRAINING AND EDUCATION
International Neuroscience Doctoral Programme (INDP)
Programme Director
Zachary Mainen
Programme Coordinator
Zachary Mainen
Administrative Assistant
Alexandra Piedade
The International Neuroscience Doctoral Programme (INDP) aims to train
students to perform innovative and integrative research into the biological
bases of behaviour. During the first year, students attend courses organized
by a combination of internal faculty and invited international researchers.
This initial training phase aims at providing students with a broad background
and common language in biology and neuroscience. The curriculum
emphasizes active participation, discussion and practical exercises. The
goal is to develop critical and creative thought and to gain exposure to a
variety of perspectives on the biology of the nervous system.
Autumn courses, organized in conjunction with the in-house PIBS programme, focus on general biological principles. Spring courses concentrate on
neuroscience, including physiology, development, sensory and motor systems,
learning, social behaviour and cognition. There is a strong quantitative
component to the curriculum, including programming, data analysis
and modeling.
At the end of the first year, students choose a thesis laboratory guided by
faculty, the programme director and neuroscience core faculty. In 2010, the
INDP entered its fourth year. A total of 40 students were enrolled, including
8 first-year students, 12 students performing thesis research abroad and
20 developing their research in CNP laboratories at the IGC.
54
2010 Students
•Bruno Miranda
MD, Medicine
University of Lisbon, Portugal
•Ana Carolina de Sousa
BS, Biotechnology
Universidade Lusofona de Humanidades e Tecnologias, Portugal
•Gustavo Mello
Master in Psychology/Psychobiology
ISPA - Insituto Superior de Psicologia Aplicada, Portugal
•Gonçalo Lopes
Computer Science
Universidade Nova de Lisboa, Portugal
•Ivo Marcelo
Biological engineering
Instituto Superior Técnico of Technical University of Lisbon, Portugal
•Raimundo Coelho Leong
Master in Mathematics
Instituto Superior Técnico of Technical University of Lisbon, Portugal
•Tiago Marques
Master in Physics/Engineering
Instituto Superior Técnico of Technical University of Lisbon, Portugal.
•Simone Lackner
Master in Molecular Biology
Universität Wien, Austria
2009 Students
•Ali Ozgur Argunsah
Hippocampal synaptic plasticity induced by natural spike trains
Laboratory of I. Israely, Champalimaud Neuroscience Programme, Instituto
Gulbenkian de Ciência, Portugal
•Andreia Cruz
Lessons from others: a study of the mechanisms underlying social
learning
Laboratory of M. Moita, Champalimaud Neuroscience Programme, Instituto
CNP at the IGC
55
•Anna Hobbiss
Clustered plasticity as a model for micro-rewiring
Laboratory of I. Israely, CNP at the IGC
•Diogo Peixoto
Dynamics of neural activity in LIP during decision-making
Laboratory of W. Newsome, Stanford Univ., USA
•Elizabeth Rickenbacher
Social modulation of fear extinction
Laboratory of M. Moita, CNP at the IGC
•David Raposo
The integration of evidence across modalities in the brain
Laboratory of A. Churchland, Cold Spring Harbor Laboratory, USA
•Niccolò Bonacchi
Context dependent modulation of value
Laboratory of Z. Mainen, Champalimaud Neuroscience Programme,
Instituto Gulbenkian de Ciência, Portugal
•Pedro Garcia da Silva
Neuromodulatory enhancement of odor representations in the rodent
olfactory bulb
Laboratory of F. Albeanu, Cold Spring Harbor Laboratory, USA
•Raquel Abreu
Somatostatin-expressing neurons of the PreBötzinger Complex
underlying Central Sleep Apnea
Laboratory of J. Feldman, UCLA, USA
•Sevinç Mutlu
Cortical dynamics of excitation and inhibition during passive and
active perception
•Simone Latkolik
Modulation of striatal network activity by gap junctions and their
role in interval timing behavior
Laboratory of J. Paton, Champalimaud Neuroscience Programme, Instituto
56
•Thiago Gouvêa
Motivational state modulation of decision making: reward expectation,
phasic dopamine and choice accuracy
2008 Students
•André Mendonça
Attentional modulation of odor discrimination in rodents
•Ana Rita Fonseca
Neural Mechanisms of Action Inhibition and Generation
Laboratory of Z. Mainen, Champalimaud Neuroscience Programme, Instituto Gulbenkian de Ciência, Portugal
•Clara Ferreira
The role of octopaminergic neurons in appetitive olfactory learning
and memory in Drosophila melanogaster
Laboratory of G. Miesenböck, University of Oxford, United Kingdom
•Fernando Santos
Neuronal ensemble selection and competition during motor skill
learning
Laboratory of R. Costa, Champalimaud Neuroscience Programme, Instituto
•João Marques
Understanding the Neural Mechanisms that Control Speed in Zebrafish
Larvae
Laboratory of M. Orger, Champalimaud Neuroscience Programme, Instituto
•Ana Pereira
Sound discrimination in fear conditioning: an interaction between
cortical and thalamic auditory structures
•Ana Isabel Amaral
A Bayesian approach to audio-hallucinatory perception using oddball
paradigm
Laboratory of D. Langers, Dep. of Otorhinolaryngology, University of
Groningen, The Nederlands
57
•Scott Rennie
The neural basis of social decision making, Rodents playing an
iterated stag hunt game
•Ana Mafalda Vicente
Neural Mechanisms Underlying The Shift Between Goal-Directed and
Habitual Actions
•Dennis Herrmann
Functional Architecture of the Neural System Controlling Female
Reproductive Behavior in Drosophila melanogaster
Laboratory of L. Vasconcelos, Champalimaud Neuroscience Programme,
2007 Students
•Patrício Simões
The Influence of Phase Change on Learning and Memory in Desert
Locusts
Laboratory of J. Niven, Department of Zoology, University of Cambridge, UK
•Isabel Henriques
Hydrogen Sulphide Mechanisms in Acute Cerebral Ischemia
Laboratory of J. Ferro, Universidade Autónoma de Madrid, Spain
•Rodrigo Abreu
Neuronal and endocrine mechanisms underlying cognitive appraisal
and social modulation of behaviour in zebrafish (Danio rerio)
Laboratory of R. Oliveira,
Champalimaud Neuroscience Programme,
•José Joaquim Fernandes
Neural correlates of hierarchical learning
Laboratory of M. Botvinick, Neuroscience Institute, Princeton University,
USA
•Íris Vilares
Uncertainty and decision making in the human brain: economics
and motor control
Laboratory of K. Koerding, Rehabilitation Institute of Chicago, Northwestern
University, USA
58
•Patrícia Correia
Serotonin function in behavior
•Maria Inês Vicente
Neural mechanisms of uncertainty in brain function and behavior
Instituto Gulbenkian de Ciência
•Pedro Ferreira
Circuit analysis of epigenetic changes during the consolidation of skills
•Margarida Agrochão
Towards an ecological approach to vision: wireless recording from
rat V1
Laboratory of M. Meister, Department of Molecular Cellular Biology,
Harvard U. Uni. University, USA
•Mariana Cardoso
Testing the Role of Cerebral Blood Flow on Neuronal Activity, in Mice
Olfactory Glomeruli
Laboratory of A. Das, Department of Neuroscience, Columbia University,
College of Physicians and Surgeons, USA
2010 Individual courses
Spring Courses in Neurosciences
11 to 16 January
Core concepts I
Rui Costa, CNP at the IGC, Susana Lima, CNP at the IGC and Marta Moita,
CNP at the IGC
18 to 23 January
Core concepts II
Rui Costa, CNP at the IGC, Susana Lima, CNP at the IGC and Marta Moita
CNP at the IGC
25 to 30 January
Evolution & development I
Luisa Vasconcelos CNPat theIGC, Joshua Corbin George Washington
University
59
1 to 6 February
Evolution & development II
Luisa Vasconcelos, CNP at IGC
Chris Braun, Hunter College and Georg Striedter, University of California at
Irvine
8 to 13 February
Cellular physiology
Joe Paton, CNP at the IGC
Kevin Franks, Columbia, Josh Dudman, HHMI, JFRC and Guillaume Dugué,
CNP at the IGC
22 to 27 February
Learning & plasticity I
Marta Moita CNP at the IGC and Inbal Israely CNP at the IGC
Martha Constantine-Paton, MIT and Steven Kushner, Erasmus Medical
Center, Rotterdam
1 to 6 March
Learning & plasticity II
Marta Moita, CNP at the IGC and Inbal Israely, CNP at the IGC
Allan Hobson, Harvard Medical School, Richard Morris, University of
Edinburgh and Bruno da Silva, University of Edinburgh
8 to 13 March
Metabolism
Carlos Ribeiro, CNP at the IGC
Leon Avery, University of Texas, Southwestern
15 to 20 March
Foraging
Carlos Ribeiro, CNP at the IGC and Rui Costa, CNP at the IGC
22 to 27 March
Action
Rui Costa, CNP at the IGC
Jose Carmena, University of California at Berkeley, Joseph McIntyre,
Université Paris Descartes and Chris de Zeeuw, Erasmus University
1 to 7 April
Social behavior
Susana Lima, CNP at the IGC and Zach Mainen, CNP at the IGC
Ken Harris, Imperial College and Marta Moita, CNP at the IGC
60
12 to 17 April
Sense and Systems
Joe Paton, CNP at the IGC, Brian Lau, Columbia, and Kenway Louie, NYU,
David Freedman, U. Chicago and Anitha Pasupathy, U. Washington
19 to 24 April
Attention and Cognition
Joe Paton, CNP at the IGC, Leo Sugrue, Stanford and Greg Corrado Stanford/IBM
Michael Goldberg, Columbia and Kacey Ballard, Stanford
26 April to 1 May
The Basics of Experimental Neuroscience
Zach Mainen, CNP at the IGC.
Adam Kampff, Florian Engert, Bence Ölveczky, and Rajesh Poddar, Harvard
3 to 8 May
Techniques: Imaging, Ethology & Physiology
Zach Mainen, CNP at the IGC. Adam Kampff, Florian Engert, Bence Ölveczky,
Rajesh Poddar, Michael Orger, Harvard
10 to 15 May
Imaging projects
Zach Mainen CNP at the IGC
Adam Kampff, Harvard and Brian Keeley, Pitzer College
17 to 22 May
Bayesian brain
Zach Mainen CNP at the IGC
Alex Pouget, University of Rochester and Jeff Beck, UCL, Gatsby
Autumn Courses in Integrative Biology
13 September – 17 September
Arrival and orientation week
Thiago Carvalho, IGC and Zachary Mainen, CNP at the IGC
António Coutinho, IGC, Zach Mainen CNP at the IGC, Élio Sucena, IGC
Paul Bush and Rita Venturini, USA
20 September – 24 September
The History of Biological Concepts
Thiago Carvalho, IGC
Jonathan Howard, University of Cologne, Lars Jansen, IGC, Christen Mirth,
IGC, Anthony Dean, Univ. of Minnesota, Alekos Athanasiadis, IGC, Mónica
Dias, IGC, José Leal, IGC, Joe Paton, CNP at the IGC, Fern Elsdon-Baker,
British Council
61
27 September – 8 October
Biology & Computation 101
Christian Machens, ENS, Paris
Alfonso Renart, CNP
11 October – 15 October
Within Cells
Lars Jansen, IGC
Robin Allshire, Wellcome Trust, Edinburgh, Monica Dias, IGC, Miguel
Godinho, IGC, Catarina Henriques, IGC, José Leal, IGC, Jon Pines, Gurdon
Institute, Cambridge, Minoo Rassoulzadega, INSERM, Nice and Jagesh Shah,
Harvard Medical School
18 October – 22 October
Between Cells
António Jacinto, IGC
Vassili Kostorou , Fleming Biomedical Research Center, Greece, Soren
Prag, IMM
Christos Zerva, Biomedical Research Foundation, Greece, Rita Fior, IMM,
Florence Janody, IGC, Leonor Saude, IMM, Jerome Solon, EMBL, Heildelberg,
Joaquin Leon, IGC, Catarina Certal, IGC, Susana Lopes, IMM
1 November – 5 November
Evolution I
Isabel Gordo, IGC
Guillaume Martin, Montpellier, Patricia Brito, IGC, Lilia Perfeito, University
of Cologne, Ana Margarida Sousa, IGC, Ivo Chelo, IGC.
Evolution II
Patricia Beldade, IGC and Christen Mirth, IGC
Michael Akam, Cambridge, Élio Sucena, IGC, Johannes Jaeger, EMBL,
Heidelberg,
Christian Braendle, Nice University.
Neuro-Development I Joshua Corbin, CNR
Carlos Ribeiro, CNP at IGC and Luisa Vasconcelos, CNP at IGC
Neuro-Development I
Carlos Ribeiro, CNP at IGC and Luisa Vasconcelos CNP at IGC
Élio Sucena, IGC
62
29 November – 10 December
Hypothesis Driven Research
Rui Martinho, IGC and Vasco Barreto, IGC
Michael Lynch, Indiana University, Donald Rio, University of California,
Berkeley and Nina Papavasiliou, Rockefeller University
13 December – 17 December
INDP Projects
Zach Mainen CNP at IGC
Christian Machens, ENS, Paris and Alfonso Renart, CNP
WORKSHOPS, MEETINGS AND SEMINARS
Imaging Structure and Function in the Zebrafish Brain
European Zebrafish Symposium
13 December – 15 December
Organizers
Rainer Friedrich, Friedrich Miescher Institute, Basel, Switzerland
Michael Orger, Champalimaud Neuroscience Programme, Lisbon, Portugal
The zebrafish model was originally conceived as an ideal system to study
neural circuits underlying behaviour. That vision is bearing fruit now
more than ever, as light has become one of the most important tools for the
neuroscientist. Optical approaches are used not only to visualize neurons,
but also to record and control their activity, and the small, transparent
brain of the zebrafish is the perfect place to exploit the potential of these
developments.
Europe is home to a rapidly growing number of groups that use optical
approaches to study the anatomical and functional organization of the
zebrafish nervous system. This symposium will bring new and established
investigators together for a discussion of recent advances, current endeavors,
and future challenges. Emphasis will be placed on opportunities for open
discussion with the aim of fostering cooperation and collaborations between
European labs.
Seminars
January 2010
Domingos Henrique
Fri 08/01/10
Ionians, IGC
Welcome to Notchland
63
Karel Svoboda
Fri 15/01/10
Ionians, IGC
The neural circuits underlying somatosensation
Rui Costa
Tue 19/01/10
Ionians, IGC
Generating and Sequencing Actions
Charles Zuker
Fri 22/01/10
Ionians, IGC
From the Tongue to the Brain: The Biology of Mammalian Taste
Bill Hansson
Wed 27/01/10
Ionians, IGC
Evolution of Olfaction
February 2010
Alexander Friedman
Mon 15/02/10
Ionians, IGC
Behavioral “re-programming” through pattern stimulation of the
neuronal tissue
Robert Horvitz
Tue 23/02/10
Ionians, IGC
The Genetic Control of Programmed Cell Death in C. elegans
March 2010
Richard Morris
Fri 05/03/10
Ionians, IGC
Memory Consolidation: Synaptic Tagging and Schemas
Leon Avery
Thu 11/03/10
Ionians, IGC
Behavioral Strategies in C elegans
64
Dinu Florin Albeanu
Thu 25/03/10
Ionians, IGC
Understanding neuronal circuits in the mammalian olfactory bulb
April 2010
Andrew Poulos
Wed 07/04/10
Ionians, IGC
Pathways to Fear, Memory & Trauma
Michael Goldberg
Fri 23/04/10
Ionians, IGC
Hering and Helmholtz were both right: two mechanisms for spatial
accuracy in the parietal cortex
Robert Malinow
Tue 27/04/10
Ionians, IGC
Synapses in normal and diseased brain function
May 2010
Dave Lovinger
Mon 03/05/10
Ionians, IGC
Synaptic Plasticity in Striatum: Substrates for Action Learning?
Cristina Marquez
Wed 05/05/10
Ionians, IGC
Mad, Bad or Sad? Neural correlates of abnormal aggression following
peripubertal stress in rats
Rainer Friedrich
Thu 06/05/10
Ionians, IGC
Neuronal circuits and computations in the olfactory system
June 2010
Kamal Sen
Fri 11/06/10
Ionians, IGC
Neural discrimination of complex natural sounds in songbirds
65
July 2010
Ekaterina Vinnik
Mon 12/07/10
Ionians, IGC
Hippocampal representation of sound-guided behavior
Pavle Itskov
Mon 12/07/10
Ionians, IGC
Texture coding in rat brain: From the neuronal code for roughness
in the barrel cortex to persistent and independent traces of stimulus
and reward location in hippocampus
Carlos Ribeiro
Tue 13/07/10
Ionians, IGC
The Molecular and Neuronal Control of Nutrient Choice in Drosophila
Stefan Thor
Fri 23/07/10
Ionians, IGC
From Progenitor to Unique Neuron: Cell Specification by the
Integration of Temporal and Positional Cues
September 2010
Laszlo Tirian
Thu 30/09/10
Ionians, IGC
Toward understanding the genetic control of male courtship
behaviour in Drosophila
October 2010
Isabel Campos
Tue 12/10/10
Ionians, IGC
Embryonic epithelia wound healing: a genetic approach in Drosophila
November 2010
Josh Corbin
Thu 18/11/10
Ionians, IGC
Embryonic patterning mechanisms for constructing the mammalian
limbic system
66
Kathrin Steck
Mon 29/11/10
Ionians, IGC
Smells like home: Olfactory orientation in desert ants
December 2010
Rui Oliveira
Tue 07/12/10
Ionians, IGC
67
4.1 Programa Doutoral para Médicos
4.2 Simpósios e Reuniões
4.2.1 2010 Champalimaud Cancer Centre Symposium
68
A Fundação deu continuidade em 2010 ao seu Programa em Cancro, com
especial ênfase no estudo, na prevenção e no tratamento das metástases.
Prof. James Watson, Presidente
do Conselho Científico da Fundação
Champalimaud, na abertura do 2010
Champalimaud Cancer Centre
Symposium
As colaborações com os responsáveis destes Programas encontram-se
detalhadas de seguida nos seus relatórios em língua inglesa.
4.1Programa Doutoral para Médicos
O Programa Gulbenkian de Formação Médica Avançada, da iniciativa
da Fundação Calouste Gulbenkian e com a colaboração da Fundação
Champalimaud, iniciou em 2010 a sua terceira edição.
Nesta edição, a Fundação Champalimaud atribuiu uma bolsa a uma médica
especialista em gastrenterologia, que iniciou o programa de formação
em Setembro. Esta médica junta-se a outros bolseiros que receberam da
Fundação Champalimaud este programa.
Em Maio de 2010 foi feita uma nova avaliação do Programa pelo External
Advisory Board, que foi globalmente muito positiva, realçando a sua qualidade
excepcional e o cumprimento dos seus objectivos, particularmente a promoção
de projectos de investigação de clínicos-investigadores para obtenção do
grau de Doutor.
69
4.2Simpósios e Reuniões
4.2.12010 Champalimaud Cancer Centre Symposium
A 6 de Outubro, a Fundação acolheu figuras proeminentes nesta área para um debate sobre investigação oncológica e respectivos tratamentos
num encontro intitulado “Curing Cancer”, organizado pelo Prémio Nobel e
Presidente do Conselho Científico da Fundação, James Watson. O Simpósio
teve início com uma intervenção da Presidente da Fundação, Dra. Leonor
Beleza, que recebeu os participantes no recém-inaugurado Champalimaud
Centre for the Unknown. Expressou a importância deste encontro, referindo
que representava a primeira actividade científica a ter lugar no novo centro.
No seguimento das palavras de abertura da Dra. Leonor beleza, foram
iniciados os trabalhos com as seguintes as intervenções:
James D. Watson, Chancellor Emeritus, Cold Spring Harbor Laboratory,
Nova Iorque, EUA: “Cancer Research - Past and Present”
Susan Lindquist, Membro do Whitehead Institute, Massachusetts Institute
of Technology, Cambridge, MA, EUA: “Targeting protein homeostasis:
a new strategy in cancer therapeutics”
Raghu Kalluri, Professor de Medicina, Harvard Medical School, Boston, MA,
EUA; “Mechanism and Therapy for Hypoxia Induced Metastasis”
Alan Ashworth, Director do Breakthrough Breast Cancer Research Centre, Alan Ashworth, Director do
Institute of Cancer Research, Londres, Reino Unido: “Hitting cancer where Breakthrough Breast Cancer Research
Centre, Institute of Cancer Research,
Londres, Reino Unido
it hurts: synthetic lethal approaches”
70
Paul A. Marks, Presidente Emérito do Memorial Sloan-Kettering Cancer
Center, Nova Iorque, EUA: “Targeting Histone Deacetylases as Anti-
-Cancer Drugs”
Este Simpósio realça o compromisso da Fundação Champalimaud na
investigação em cancro e na organização de encontros e simpósios, que
incluem já o “2009 Champalimaud Cancer Research Symposium”, o “73rd
Cold Spring Harbor Symposium”, patrocinado pela Fundação, um thinktank
no prestigiado Banbury Center e a conferência proferida pelo Professor
James Watson, com o título “How to Cure Cancer”. Com início das actividades
no Champalimaud Centre for the Unknown, o programa de reuniões e cursos
continuará a crescer e a desenvolver-se.
71
Champalimaud Metastasis Programmes
RESEARCH SUMMARY
Yibin Kang
Molecular Mechanism of Breast Cancer Metastasis
Group members (as of 03/2011)
Yong Wei (Post-doc)
Hanqiu Zheng (Post-doc)
Rumela Chakrabarti (Post-doc)
Mario Andres Blanco (PhD Student)
Yuling Hua (PhD Student)
Brian Ell (PhD Student)
Liling Wan (PhD Student)
Our study on Jagged1-Notch Signaling was highlighted in the cover of
the February 2011 issue of Cancer
Cell. This image shows a “vicious
cycle” of tumor-stromal signaling
events mediated by TGF-β, Notch
and IL-6 pathways in osteolytic
bone metastasis of breast cancer.
Maša Alečković (Ph.D. Student)
Min Yuan (Research Technician)
Xiang Hang (Research Technician)
Metastasis, the spread of cancer cells from the primary tumor to distant
organs, is the most dreadful development of neoplastic diseases. The
mission of our laboratory is to apply modern molecular biology, genomics,
and computational biology approaches to understand the molecular basis
of cancer metastasis. Major areas of research in our laboratory includes:
identification
and
functional
characterization
of
metastasis
genes,
pre-clinical evaluation of anti-metastasis therapeutics, development of
advanced imaging technology and non-invasive detection of tumor-stroma
interaction during metastasis, the role of miRNA in cancer progression
and metastasis, molecular characterization of mammary gland stem cells
and their link to breast tumor stem cells.
In the past year, with the support of the Champalimaud Foundation, we
have made several major breakthroughs that lead to publication of several
high impact papers in Cancer Cell, Cancer Research, etc. These studies
illustrate a novel role of Notch signaling in osteolytic bone metastasis, the
dynamic function of hypoxia in organ-specific metastasis, the surprising
function of spontaneous ploidy duplication in promoting lung metastasis, and
the first metabolomic profiling of cancer cells with progressively increasing
metastatic abilities. We have also generated the first knockout mouse
model for MTDH, a dual functional chemoresistance/metastasis gene that
we identified in 2009 in a high profile Cancer Cell cover article, to confirm
72
its crucial role in tumor progression and metastasis, , and identified SND1
as a novel MTDH interacting protein with metastasis-promoting functions.
The following summarizes our major findings in the studies of molecular
basis of breast cancer progression and metastasis that we conducted
in the past year.
Jagged1-Notch signaling in osteolytic bone metastasis.
Previous studies in our group and others have demonstrated a functional
role of the TGFβ signaling pathway in promoting bone metastasis. However,
the downstream target genes of TGFβ pathway that mediate bone metastasis
remain poorly defined. We recently identified Jagged1, a Notch pathway
ligand, as such a functional mediator for the pro-metastatic function of
TGFß. Beyond its well characterized functions in embryonic and postnatal
development, the Notch pathway has attracted increasing recognition for
its aberrant activation in cancer. Despite evidence supporting an oncogenic
role, the mechanism underlying the pathway’s contribution to metastasis
remains unknown.
In this study, we show that elevated expression of
the Notch pathway ligand Jagged1 in breast cancer is associated with
aggressive metastatic ability of tumor cells and an increased incidence of
bone metastasis. Functional studies revealed that tumor-derived Jagged1
promotes osteolytic bone metastasis by activating Notch signaling in the
supporting bone stromal components, including osteoblasts and osteoclasts.
Jagged1-Notch signaling in the tumor-bone microenvironment confers
growth advantage to tumor cells and stimulates osteolysis. Importantly,
γ-secretase inhibitor treatment reverses Jagged1-mediated bone metastasis
by disrupting the Notch pathway in bone stromal cells. These findings
elucidate a stroma-dependent mechanism for the prometastatic function
of Notch signaling in breast cancer and provide preclinical evidence for
γ-secretase inhibitors as therapeutic agents against bone metastasis.
Rabconnectin-3 is a functional regulator of mammalian Notch signaling
The Notch signaling pathway is important for cell-fate decisions in
embryonic development and adult life and has been recently shown to be
involved in the development of metastasis. Defining the functional importance
of the Notch pathway in these contexts requires the elucidation of essential
signal transduction components that have not been fully characterized.
Here, we show that Rabconnectin-3B is required for the Notch pathway
in mammalian cells. siRNA-mediated silencing of Rabconnectin-3B in
mammalian cells attenuated Notch signaling and disrupted the activation
and nuclear accumulation of the Notch target Hes1. Rabconnectin-3B
knockdown also disrupted V-ATPase activity in mammalian cells, consistent
with previous observations in Drosophila. Pharmacological inhibition of the
V-ATPase complex significantly reduced Notch signaling in mammalian cells.
73
Finally, Rabconnectin-3B knockdown phenocopied functional disruption of
Notch signaling during osteoclast differentiation. Collectively, these findings
define an important role for Rabconnectin-3 and V-ATPase activity in the
Notch signaling pathway in mammalian cells.
In vivo dynamics and distinct functions of hypoxia in primary tumor
growth and organotropic metastasis of breast cancer
Tumor hypoxia is known to activate angiogenesis, anaerobic glycolysis,
invasion and metastasis. Hypoxic gene expression profile has been linked
to poor clinical outcomes. However, a comparative analysis of the potentially
distinct functions of hypoxia in primary tumor growth and organ-specific
metastasis has not been reported. Here, we show distinct hypoxia kinetics
in tumors generated by the MDA-MB-231 breast cancer sublines with
characteristically different primary tumor growth rates and organotropic
metastasis potentials. Hypoxia-induced angiogenesis promotes both primary
tumor growth and lung metastasis but is non-essential for bone metastasis.
Microarray profiling revealed that hypoxia enhances the expression of
a significant number of genes in the lung metastasis signature, but only
activates a few bone metastasis genes, among which DUSP1 was functionally
validated in this study. Despite the different mechanisms by which hypoxia
promotes organ-specific metastasis, inhibition of HIF-1α with a dominant
negative form of HIF-1α or 2-methoxyestradiol reduced metastasis to both
lung and bone. Consistent with the extensive functional overlap of hypoxia
in promoting primary tumor growth and lung metastasis, a 45-gene hypoxia
response signature efficiently stratifies breast cancer patients with low
or high risks of lung metastasis, but not for bone metastasis. Our study
demonstrates distinct functions of hypoxia in regulating angiogenesis and
metastasis in different organ microenvironments and establishes HIF-1α as
a promising target for controlling organotropic metastasis of breast cancer.
Metabolomic changes accompanying transformation and acquisition of
metastatic potential in a syngeneic mouse mammary tumor model.
Despite decades of research, the molecular processes associated with the
breast cancer progression are still inadequately defined. In particular,
recent studies on breast cancer metastasis have focused on gene expression
changes that are associated with metastatic phenotype while alteration of
metabolic activities in metastatic cancer cells have not been analyzed in a
systemic level. Here, we focus on the systematic alteration of metabolism by
using the state of the art metabolomic profiling techniques to investigate
the changes of 157 metabolites during the progression of normal mouse
mammary epithelial cells to an isogenic series of mammary tumor cell
lines with increasing metastatic potentials. Our results suggest a two-step
metabolic progression hypothesis during the acquisition of tumorigenic and
74
metastatic abilities. Metabolite changes accompanying tumor progression
are identified in the intracellular and secreted forms in several pathways,
including glycolysis, tricarboxylic acid cycle, pentose phosphate pathway,
fatty acid and nucleotide biosynthesis and the GSH-dependent anti-oxidative
pathway. These results suggest possible biomarkers of breast cancer
progression as well as opportunities of interrupting tumor progression
through the targeting of metabolic pathways.
Organ-specific enhancement of metastasis by spontaneous ploidy
duplication and cell size enlargement.
Aneuploidy is commonly observed in breast cancer and is associated with
poor prognosis. One frequent type of aneuploidy, hypertetraploidy, may
derive from ploidy duplication of hyperdiploid cells. However, the pathological
consequences of ploidy duplication in breast cancer progression have not
been characterized. Here, we present an experimental system demonstrating
spontaneous appearance of hypertetraploid cells from organ-specific
metastatic variants of the MDA-MB-231 breast cancer cell line through
ploidy duplication in vitro and in vivo. The hypertetraploid progenies showed
increased metastatic potential to lung and brain, but not to bone, which may
be partially explained by the distinct capillary structures in these organs
that confer differential lodging advantages to tumor cells with enlarged
size. These results suggest a potential mechanistic link between ploidy
duplication and enhancement of metastatic potentials, as was observed in
previous clinical studies of breast cancer.
Genetic
disruption
of
Metadherin
suppresses
mammary
tumor
progression and metastasis in mice
Metadherin is overexpressed in 40% of breast cancer patients and
strongly associated with poor prognosis. However, evidence supporting its
involvement in autochthonous cancer models was currently lacking and
little is known about its function in normal development. Here we report the
generation of Mtdh-deficient mice and demonstrate that Mtdh is dispensable
for embryogenesis but required for optimal mammary morphogenesis. Mtdh
loss profoundly impairs tumorigenesis, tumor growth and metastasis, and
the contribution of Mtdh to mammary tumor progression may be partially
accounted by its suppression of apoptosis through potentiating the Akt
pathway. In addition, a murine Mtdh-associated gene signature predicts
clinical outcome in breast cancer patients in a manner consistent with the
tumor-promoting function of Mtdh in mice.
75
Identification of Staphylococcal nuclease domain containing 1 (SND1) as
a Metadherin-interacting protein with metastasis-promoting functions
Metastasis is the deadliest and most poorly understood feature of malignant
diseases. Recent work has shown that Metadherin (MTDH) is overexpressed
in over 40% of breast cancer patients and promotes metastasis and
chemoresistance in experimental models of breast cancer progression. Here
we apply mass spectrometry-based screen to identify Staphylococcal nuclease
domain containing 1 (SND1) as a candidate MTDH interacting protein. After
confirming the interaction between SND1 and MTDH, we tested the role of
SND1 in breast cancer and found that it strongly promotes lung metastasis.
SND1 was further shown to promote resistance to apoptosis and to repress
expression of the KiSS1 metastasis suppressor gene. Analyses of breast
cancer clinical microarray data indicated that high expression of SND1 in
primary tumors is strongly associated with reduced metastasis-free survival
in multiple large scale datasets. Thus, we have uncovered SND1 as a novel
MTDH-interacting protein and shown that it is a functionally and clinically
significant mediator of metastasis.
Research Funding
Source: NIH (NCI)
Title: Metadherin in Metastasis and Chemoresistance of Breast Cancer
Total Period: 9/1/08-8/31/13
Source: NIH
Title: The Role of miRNAs in Epithelial Mesenchymal Transition and
Metastasis Total Period: 4/1/10-3/30/15
Source: DOD Era of Hope Scholar Award
Title: Systems Biology of Breast Cancer Metastasis
Total Period: 7/1/06-6/30/11
Source: Champalimaud Foundation
Title: Champalimaud Metastasis Program at Princeton University
Total Period: 5/1/09-4/30/2014
Source: New Jersey Commission on Cancer Research
Title: Targeting Notch Signaling in Breast Cancer Metastasis
Total Period: 6/26/09-6/25/11
Source: Breast Cancer Alliance Exceptional Project Grant
Title: The role of VCAM1 in the activation of dormant breast cancer bone
micrometastasis
Total Period: 1/1/11-12/31/11
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PUBLICATIONS
Refereed Journal Articles
1. Lu X, Bennet B, Mu E, Rabinowitz J, and Kang Y. (2010) Metabolomic
profiling reveals a two-step metabolic progression model of metastatic
breast cancer. J. Biol. Chem., 285(13):9317-21.
2. Lu X and Kang Y. (2010) Epidermal growth factor signaling and bone
metastasis. Br. J. Cancer, 102(3):457-61.
3. Korpal M and Kang Y. (2010) Targeting the transforming growth factor-beta
signaling pathway as in metastatic cancer. Eur J Cancer, 46(7):1232-40.
4. Lu X, Yan C, Yuan M, Wei Y, Hu G, and Kang Y. (2010) In vivo dynamics
and distinct functions of hypoxia in primary tumor growth and
orga-notropic metastasis of breast cancer. Cancer Res., 70(10):3905-14.
(Cover highlight)
5. Matveeva O, Kang Y, Nechipurenko YD, Nemtsov VA, Spiridonov AN
and Shabalina SA. (2010) Optimization of duplex stability and terminal
asymmetry for shRNA design. PLoS One, 5(4): e10180.
6. Lu X, Lu X and Kang Y. (2010) Organ-specific enhancement of metastasis
by spontaneous ploidy duplication and cell size enlargement. Cell Res.,
20(9):1012-22.
7. Ganapathy V, Ge R, Grazioli A, Xie W, Banach- Petrosky W, Kang Y,
Lonning S, McPherson J, Yingling JM, Biswas S, Mundy GR, and Reiss
M. (2010) Targeting the transforming growth factor-β pathway inhibits
human basal-like breast cancer metastasis. Mol. Cancer., 9(1):122.
8. Sethi N and Kang Y. (2010) Dysregulation of developmental pathways in
bone metastasis. Bone, 48(1):16-22.
9. Sethi N, Yan Y, Quek D, Schupbach T, Kang Y. (2010) Rabconnectin3 is
a functional regulator of mammalian Notch signaling. J. Biol. Chem.,
285:34757-64.
10.Lu X and Kang Y. (2010) Hypoxia and hypoxia-inducible factors (HIFs):
master regulators of metastasis. Clin. Cancer Res., 16:5928-35.
11.Tamasi J, Zhang X, Lu X, Zhu J, Chen H, Tian X, Lee T-C, Threadgill DW,
Kream BE, Kang Y, Partridge NC, and Qin L. (2010) In vivo epidermal
growth factor receptor plays an anabolic role in bone metabolism.
J. Bone Miner. Res., Nov 18. [Epub ahead of print].
77
12.Tiede B and Kang Y. (2011) From milk to malignancy: the role of
mammary stem cells in development, pregnancy and breast cancer.
Cell Res., 21(2):245-57.
13.Sethi N, Dai X, Winter CG, and Kang Y. (2011) Tumor-derived Jagged1
promotes osteolytic bone metastasis of breast cancer by activating
stromal Notch signaling. Cancer Cell, 19(2):192-205. (Cover Article)
Editorial by: Tao J, Erez A, Lee B. Cancer Cell, 19(2):192-205.
14.Blanco MA and Kang Y. (2011) Signaling pathways in breast cancer metastasis – novel insights from functional genomics. Breast Cancer Res., in press.
15.Shan J, Budjiono SJ, Hu G, Yao N, Kang Y, Ju Y, and Prud’homme RK.
(2011) PEGylated composite nanoparticles containing upconverting
phosphors and meso-tetraphenyl porphine (TPP) for photodynamic
therapy. Nano Letters, in press.
16.Blanco MA, Alečković A, Hua Y, Li T, Wei Y, Xu Z, Cristea I, and Kang Y.
(2011) Identification of Staphylococcal nuclease domain containing 1
(SND1) as a Metadherin-interacting protein with metastasis-promoting
functions. J. Biol. Chem., in press.
17.Korpal M, Ell BJ, Buffa FM, Ibrahim T, Terrasa AC, Mercatali L, Khan
Z, Blanco MA, Goodarzi H, Hua Y, Wei Y, Hu G, Garcia B, Ragoussis J,
Amadori D, Harris AL, and Kang Y. (2011) Direct targeting of Sec23a
by miR-200s influences cancer cell secretome and promotes metastatic
colonization. Nature Medicine, submitted.
18.Wan L, Lu X, Yuan M, Blanco MA, Wei Y, Mellor H, and Kang Y. (2011)
Genetic disruption of Metadherin suppresses mammary tumor progression
and metastasis in mice. Genes & Dev., submitted.
19.Sethi N and Kang Y. (2011) Metastasis — from gene discovery to clinical
applications. Nature Reviews Cancer (invited review), in preparation.
Published Meeting Abstracts
Lu X, Yang Q, Yuan M, Mu E, Reiss M, Haffty B, Massagué J, Kang Y. (2010)
VCAM1 mediates the aggressive conversion of dormant breast cancer bone
metastasis by promoting angiogenesis and osteoclastogenesis. AACR 100th
Annual Meeting Denver, Colorado, USA
Sethi NS, Dai X, Winters C, Kang, Y. (2010) A Novel Role of Notch Signaling in
Breast Cancer Bone Metastasis. AACR-MRS Joint Conference on Metastasis
and the Tumor Microenvironment. Philadelphia, PA, USA.
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Sethi NS, Dai X, Winters C, Kang, Y. (2010) Jagged1 promotes osteolytic bone
metastasis via tumor-stroma interactions. 25th Annual MD-PhD Student
Conference. Keystone, Colorado, USA.
Sethi NS, Dai X, Winters C, Kang, Y. (2010) Tumor-derived Jagged1
promotes osteolytic bone metastasis of breast cancer by enganging stromal
Notch signaling. MGH-KI-Cell Press Days of Molecular Medicine: Systems
Biology Approaches to Cancer and Metabolic Disease. Karolinska Institute,
Stockholm, Sweden. Sethi NS, Dai X, Winters C, Kang, Y. (2010) Tumor-derived Jagged1 promotes
osteolytic bone metastasis of breast cancer by enganging stromal Notch
signaling.
National Student Research Forum. UTMB, Galveston, Texas,
USA.
Meetings Organized
2010 Annual Meeting of the American Association for Cancer Research
(AACR)
Washington DC, USA April 2010
Yibin Kang, Member of the Education Committee
Chair of the Workshop on the Mouse Models of Invasion and Metastasis
13th International Symposium of the Society of Chinese Bioscientists
in America
Guangzhou, China, July 2011
Yibin Kang, Co-organizer and Section Chair
11th Annual Conference of Cancer-Induced Bone Disease
Chicago, IL, November, 2011
Yibin Kang, Co-organizer and member of scientific committee
Invited presentations
Yibin Kang has given invited lectures on breast cancer metastasis in
the following meetings and seminars:
1. University of Colorado Cancer Center, Denver, CO (2/10/2010)
2. Emory University Winship Cancer Institute, Atlanta, GA (3/19/2010)
3. Paterson Institute for Cancer Research and Manchester Breast Centre,
University of Manchester, United Kingdoms (3/23/2010)
79
4. 101st Annual Meeting of American Association for Cancer Research,
Washington, DC (4/18/2010)
5. A. C. Camargo Cancer Hospital and Antonio Prudente Cancer Research
Center, São Paulo, Brazil (4/30/2010)
6. Banbury Tumor Microenvironment and Metastasis Conference, Cold
Spring Harbor Laboratory, Cold Spring Harbor, NY (5/7/2010)
7. Rolanette and Berdon Lawrence Bone Disease Program, Baylor College
of Medicine and M.D. Anderson Cancer Center, Houston, TX (5/28/2010)
8. 19th Annual Meeting of Japanese Association of Metastasis Research,
Kanazawa, Japan (6/16/2010)
9. Xiamen University, Xiamen, China (6/22/2010)
10.Zhejiang University, Zhejiang, China (6/25/2010)
11.2010 Bladder Cancer Think Tank Meeting, Traverse City, MI (8/6/2010)
12.Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA
(8/24/2010)
13.McArdle Cancer Research Seminar Series, University of Wisconsin
at Madison (9/8/2010)
14.Joint Metastasis Research Society-AACR Conference, Philadelphia, PA
(9/13/2010)
15.Tianjin University General Hospital, Tianjin, China (10/19/2010)
16.Ohdang Plenary Lecture , 2010 Annual Convention of the Pharmaceutical
Society of Korea, Cheongju, Republic of Korea (10/21/2010)
17.Korea Advanced Institute of Science and Technology, Deajeon, Republic
of Korea (10/22/2010)
18.NSF workshop “Physics of Metastasis”, Washington DC (11/1/2010)
19.Department of Biochemistry, State University of New York at Buffalo and
Roswell Park Cancer Center, Buffalo, NY (11/9/2010)
20.Breast Cancer Program, Karmanos Cancer Institute, Wayne State
University, Detroit, MI (11/18/2010)
21.Amgen Inc, Thousand Oaks, CA (12/10/2010)
22.International symposium: “Breast cancer: today and tomorrow a multidisciplinary approach”, Forlì, Italy (12/16/2010)
23.Champalimaud Cancer Centre Symposium, Champalimaud Foundation,
Lisbon, Portugal (1/14/2011)
24.Women’s Cancer Research Program, Fox Chase Cancer Center,
Philadelphia, PA (1/27/2011)
80
25.Department of Physiology, Tufts University School of Medicine, Boston,
MA (3/8/2011)
Yibin Kang has been invited to give lecture at the following upcoming
meetings and seminars:
26.Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV (5/11/2010)
27.Department of Hematology and Oncology, University of Freiburg, Germany
(5/20/2011)
28.The Gordon Research Seminar (GRS) and Gordon Research Conference
(GRC) on “Bones & Teeth”, Les Diablerets, Switzerland (6/18/2011)
29.Champalimaud-TuMic Metastasis Research Meeting, Lisbon, Portugal
(6/26/2011)
30.13th International Symposium of the Society of Chinese Bioscientists
in America, Guangzhou, China (7/28/2011)
31.The 9th Biannual Conference of Chinese Biological Investigator Society,
ZhangJiaJie, China (7/31/2011)
32.2011 FASEB meeting on TGF-β Signaling in Development and Disease,
Lucca, Italy (8/21/2011)
33.Department of Pediatric Oncology, M.D. Anderson Cancer Center, Houston,
TX (9/14/2011)
34.11th Annual Conference of Cancer-Induced Bone Disease, Chicago, IL
(11/29/2011)
35.2nd International Conference: Translational Research in Oncology, Forlì,
Italy (5/9-11/2012)
36.Fourth International Conference on Osteoimmunology: Interactions of
the Immune and Skeletal Systems, Corfu, Greece (6/18/2012)
81
RESEARCH SUMMARY
Raghu Kalluri M.D., Ph.D.
Professor of Medicine
Harvard Medical School
Champalimaud Cancer Programme at
Beth Israel Deaconess Medical Center and Harvard Medical
School, Boston
Group members
Hikaru Sugimoto, MD, PhD (T32 NIH Trainee)
Tahereh Ghaziani, MD (T32 NIH Trainee)
Saila Ventrapragada, MD (T32 NIH Trainee)
Vesselina Cooke, PhD (Post-Doctoral Fellow, NIH-NRSA Fellow)
Akane Kizu, PhD (Post-Doctoral Fellow, Japanese Endocrine
Society Fellow)
Targeting mesenchymal cells in
breast tumors
Ignacio Revuelta, MD (Post Doctoral Fellow, Spanish Society
of Nephrology Fellow)
Genta Maeda, PhD (Post Doctoral Fellow, Japanese Cancer Society Fellow)
Noritoshi Kato, MD, PhD (Post Doctoral Fellow, Japanese Society
Gangadhar Taduri, MD (Post-Doctoral Fellow, International Society
Valerie LeBleu, PhD (Instructor; T32 NIH Trainee)
Sonia Melo, PhD (Post Doctoral Fellow, EMBO Fellow)
Joyce Tse (Harvard PhD student; Department of Defense Trainee)
Sylvia Vong (Harvard PhD student)
Doruk Keskin (Harvard PhD student)
Zainab Khan (Harvard PhD student)
Annie Vo (Harvard PhD student)
Cristina Espinosa Da Silva (Laboratory Manager)
Overall Summary:
The central mission of the champalimaud metastasis program at the Beth
Israel Deaconess Medical Center and Harvard Medical School is cancer
research and education.
The goal of our laboratory is to determine
82
the contribution of tumor microenvironment in cancer progression and
metastasis. This effort is coupled with our regenerative biology studies to
evaluate the response our body to repair tissue damage, as also observed
in tumor growth. The Champalimaud metastasis program at the Beth Israel
Deaconess Medical Center and Harvard Medical School specifically focuses
on the elucidating role of fibroblasts and other stromal cells in metastasis
associated with breast, prostate, pancreatic and skin cancer. We use mouse
models coupled with human tumor samples to unravel new pathways and
identify new therapy targets against metastatic cancer. In addition to the
research activity, our Champalimaud metastasis program serves as an
important base for education and scientific training of scientists, students
and trainees from Portugal.
Research Projects:
1. To determine the role of Fibroblasts in Cancer Progression and
Metastasis
2. To determine the role of Metabolism in Cancer Progression and
Metastasis
3. To identify neew therapies for Metastasis and pre-clinical testing in
genetic mouse models
Current Research Funding
– EU-Indigo grant. This grant is for two years between Champalimaud
Foundation (Lisbon, Portugal), German Cancer Foundation-DKFZ
(Heidelberg, Germany) and MNJ Cancer Hospital (Hyderabad, India.
The project will study Genetics of Stromal cells in Breast Cancer. This
project began in September of 2010.
– NIH RO1 DK 55001. Assembly of Type IV Collagen in Health and Disease.
PI: Raghu Kalluri
– NIH RO1 CA 125550. Role of fibroblasts in cancer. PI: Raghu Kalluri
– NIH RO1 CA 155370. Targeting pericytes in cancer. PI: Raghu Kalluri
– NIH RO1 CA 151925. Role of stromal cells in Pancreatic Ductal Adenocarcinoma. PI: Raghu Kalluri
– NIH RO1 DK 81576. Epigenetics in Fibroblasts. PI: Raghu Kalluri
– Infinity Pharmaceuticals. Role of Sonic Hedgehog Signaling in cancer
PI: Raghu Kalluri
– Genentech. Biomarkers of anti-angiogenic drugs. PI: Raghu Kalluri
– Harvard Stem Cell Istitute. Stem cells in tissue regeneration. PI: Raghu
Kalluri
– The also had 12 fellowship grants from different organizations to support
the salaries and research/education activities of the trainees.
83
PUBLICATIONS (2010-2011)
1. Lee SB, Wong AP, Kanasaki K, Xu Y, Shenoy VK, McElrath TF,
Whitesides GM, Kalluri R. Preeclampsia. 2-Methoxyestradiol Induces
Cytotrophoblast Invasion and Vas-cular Development Specifically under
Hypoxic Conditions. Am J Pathol. 2010Jan 14.
2. Flier SN, Tanjore H, Kokkotou EG, Sugimoto H, Zeisberg M, Kalluri R.,
Identification of epithelial to mesenchymal transition as a novel source
of fibroblasts in intestinal fibrosis. J Biol Chem. 2010 Apr 2.
3. Bechtel W, McGoohan S, Zeisberg EM, Müller GA, Kalbacher H, Salant
DJ, Müller CA, Kalluri R, Zeisberg M. Methylation determines fibroblast
activation and fibrogenesis in the kidney. Nat Med. 2010 Apr 25.
4. Hamano Y, Okude T, Shirai R, Sato I, Kimura R, Ogawa M, Ueda Y,
Yokosuka O, Kalluri R, Ueda S.Lack of Collagen XVIII/Endostatin
Exacerbates Immune-Mediated Glomerulonephritis. J Am Soc Nephrol.
2010 Jul 8.
5. Lebleu V, Sund M, Sugimoto H, Birrane G, Kanasaki K, Finan E, Miller CA,
Gattone VH 2nd, McLaughlin H, Shield CF 3rd, Kalluri R. Identification
of NC1 domain of {alpha}3 chain as critical for {alpha}3{alpha}4{alpha}5
type IV collagen network assembly. J Biol Chem. 2010 Sep 16.
6. Medici D, Shore EM, Lounev VY, Kaplan FS, Kalluri R, Olsen BR.
Conversion of vascular endothelial cells into multipotent stem-like cells.
Nat Med. 2010 Dec;16(12):1400-6.
7. Bravo-Nuevo A, Sugimoto H, Iyer S, Fallon Z, Lucas JM, Kazerounian S,
Prendergast GC, Kalluri R, Shapiro NI, Benjamin LE. RhoB Loss Prevents
Streptozotocin-Induced Diabetes and Ameliorates Diabetic Complications
in Mice. Am J Pathol. 2011 Jan;178(1):245-52.
8. Melo S, Villanueva A, Moutinho C, Davalos V, Spizzo R, Ivan C, Rossi S,
Setien F, Casanovas O, Simo-Riudalbas L, Carmona J, Carrere J, Vidal A,
Aytes A, Puertas S, Ropero S, Kalluri R, Croce CM, Calin GA, Esteller M.
Small molecule enoxacin is a cancer-specific growth inhibitor that acts by
enhancing TAR RNA-binding protein 2-mediated microRNA processing.
Proc Natl Acad Sci U S A. 2011 Feb 28. [Epub ahead of print]
9. Teng Y, Kanasaki K, Bardeesy N, Sugimoto H, Kalluri R. Deletion of
Smad4 in Fibroblasts Leads to Defective Chondrocyte Maturation and
Cartilage Production in a TGF Type II Receptor Independent Manner.
Biochem Biophys Res Commun. 2011 Mar 2. [Epub ahead of print]
10.Ayala de la Pena F, Kanasaki K, Kanasaki M, Tangirala N, Maeda G, Kalluri R.
Loss of p53 and acquisition of angiogenic microRNA profile is insufficient
to facilitate progression of bladder urothelial carcinoma in situ to invasive
carcinoma. J Biol Chem. 2011 Mar 9. [Epub ahead of print]
11.Xie l, Duncan, D, Lively, J, Hynes, RO, Hanahan, D, Kalluri R, Systemic
Angiogenesis Balance Controls the Rate of Cancer Progression. Proc.
Natl. Acad. Sci. USA (In Press).
84
12.Polyak K, Kalluri R. The Role of the Microenvironment in Mammary
Gland Development and Cancer. Cold Spring Harb Perspect Biol. 2010
Jun 30.
13.Krenning G, Zeisberg EM, Kalluri R. The origin of fibroblasts and
mechanism of cardiac fibrosis. J Cell Physiol. 2010 Jul 15.
14.Shenoy V, Kanasaki K, Kalluri R. Pre-eclampsia: connecting angiogenic
and metabolic pathways. Trends Endocrinol Metab. 2010 Jun 18.
15.Nataraj D, Ernst A, Kalluri R. Idiopathic pulmonary fibrosis is associated
with endothelial to mesenchymal transition. Am J Respir Cell Mol Biol.
2010 Aug;43(2):129-30.
16.Wiig H, Tenstad O, Iversen PO, Kalluri R, Bjerkvig R. Interstitial fluid:
the overlooked component of the tumor microenvironment? Fibrogenesis
Tissue Repair. 2010 Jul 23;3(1):12.
17.Wiig H, Keskin, D and Kalluri R Lymphangiogenesis and the contribution
of extracellular matrix. Matrix Biology epub ahead of print.
18.Force T, Bonow RO, Houser SR, Solaro RJ, Hershberger RE, Adhikari B,
Anderson ME, Boineau R, Byrne BJ, Cappola TP, Kalluri R, LeWinter
MM, Maron MS, Molkentin JD, Ommen SR, Regnier M, Tang WH, Tian R,
Konstam MA, Maron BJ, Seidman CE. Research priorities in hypertrophic
cardiomyopathy: report of a Working Group of the National Heart, Lung,
and Blood Institute Circulation. 2010 Sep 14;122(11):1130-3.
19.Shenoy V, Kanasaki K, Kalluri R. Pre-eclampsia: connecting angiogenic
and metabolic pathways Trends Endocrinol Metab. 2010 Sep;21(9):529-36.
20.Keskin D, Kalluri R. NF-kappaB-induced chromatin remodeling regulates
angiogenesis. Blood 2010 Jul 22;116(3):312-3.
21.Zeisberg EM, Kalluri R. Origins of cardiac fibroblasts. Circ Res. 2010
Nov 26;107(11):1304-12.
22.Lee SB, Kalluri R. Mechanistic connection between inflammation and
fibrosis. Kidney Int. 2010 Dec;78 Suppl 119:S22-6.
23.Hertig A, Flier SN, Kalluri R. Contribution of epithelial plasticity to renal
trans-plantation-associated fibrosis. Transplant Proc. 2010 Nov;42(9
Suppl):S7-12.
85
MEETINGS, COURSES, SEMINARS (2010-2011)
Meeting Organized/Co-organized
IChampalimaud Foundation Tumor Microenvironment and Metastasis
Meeting
The Banbury Center, Cold Spring Harbor Laboratory, New York, USA
May 5-7, 2010
ISN Nexus Symposium on Fibrosis
Crowe Plaza Hotel, Geneva
June 30-July 2, 2010
4th Mayo Clinic Angiogenesis Symposium: Bench-side Stimulus
for Translational Medicine.
Mackinac Island, Michigan, USA
August 27, 2010 - August 29, 2010
Inaugural Champalimaud Symposium on ‘Curing Cancer’
Lisbon, Portugal
MRS International Meeting on Metastasis, June 2011.
Libson, Portugal
5th TEMTIA EMT Meeting
Singapore
June-July, 2011
Courses
– Harvard Medical School (HMS) Ethics course: The Conduct of Science
– HMS 1st Year pathology (IMP) course
– HMS/BBS Micro 230, 1st year graduate program course
– HMS/MIT Renal pathophysiology course
– HMS 1st year Scholars in Medicine course. Tutor and course director
– University of Coimbra oncobiology course for graduate students
Education and Scientific Training of Portuguese Scientists and
Students
– Sergio Diaz, PhD: Dr. Diaz is a scientist at the Oncology Insitiute in
Lisbon. Dr. Diaz spent 4 months in our laboratory in 2010 as a visiting
scientist and participated in cancer research being conducted as part of
the Champalimaud Metastasis Program at BIDMC and HMS.
86
– Sonia Melo, PhD: Dr. Melo is a graduate of the Porto GABBA graduate
program and trained in Barcelona and recently joined our laboratory as a
research fellow. She just received the prestigious EMBO fellowship for her
research work.
Awards
2010 Fellow, American Society for Clinical Investigation
2010 Folkman Award Lectureship, 4th Mayo Cinic Angiogenesis Symposium
Seminars
Invited Speaker
2010 NCI’s National Tumor Microenvironment Network Meeting, Nashville, TN
2010 Indian School of Business, Hyderabad, India
2010 Albert Einstein College of Medicine Cardiology Seminar Series,
New York City, NY
2010 Lecture/Session Chairperson, AACR Special Conference: EMT and
Cancer Progression and Treatment, Arlington, VA
2010 Symposium on Current Topics in Fibrosis, Amersfoort, Netherlands
2010 International Transplant Symposium, Sorrento, Italy
2010 University of Goettingen, Goettingen, Germany
2010 Stower’s Institute for Biomedical Research, Kansas City, KS
2010 Meet the Expert/Lecture, 2010 AACR Annual Meeting, Washington DC
2010 First International Course on Advances in Cellular and Molecular
Biology, Sao Paulo, Brazil
2010 Cold Spring Harbor Laboratory-Banbury Meeting on Tumor Micro-environment and Metastasis
2010 Korean Society of Nephrology, Seoul, Korea
2010 2nd EMBO Conference on Cellular Signaling and Molecular Medicine,
Dubrovnik, Croatia
2010 Short Course in Cancer Biology, Eppley Institute for Research in Cancer,
Omaha, Nebraska
2010 Canadian Society of Nephrology, Montreal, Canada
2010 ISN Nexus Symposium on Kidney Fibrosis, Geneva, Switzerland
2010 Roche Symposium on Angiogenesis Biomarkers, Vancouver, Canada
2010 4th Mayo Clinic Angiogenesis Symposium, Mackinac Island, MI, USA
2010 Karolinska Institute, Stockholm, Sweden
2010 Annual Meeting of Brazilian Society of Nephrology, Vitoria, Brazil
2010 Cancer Symposium, Eli Lily Pharmaceuticals, Indianapolis, IN, USA
2010 Special Lecture, Toronto Transplant Institute at University of Toronto,
Toronto, Canada
87
2010 Fibrosis Workshop Organized by Roche Pharmaceuticals, New York City,
NY, USA
2010 17th Heidelberger Symposium on Cancer Research, Coimbra, Portugal
2010 American Society of Nephrology Annual Meeting, Denver, Colorado
2010 Inaugural Champalimaud Cancer Centre Symposium, Lisbon, Portugal
2010 Director’s Lecture, UCSD Cancer Center, La Jolla, California
2010 MITRAL meeting in Cardiovascular Research, Milan, Ital
2010 Amazon Project in Cancer, Palermo, Italy
2010 International Meeting on Tumor Microenvironment and Angiogenesis,
Ascona, Switzerland
2010 University of Madrid Cancer Center and Institute for Cancer Research,
Madrid, Spain
2011 Co-organizer, Session Chair and Lecture, Folkman Memorial Symposium, Lisbon, Portugal
2011 Keystone Meeting on Epithelial Plasticity and Epithelial to Mesenchymal
Transition, Vancouver, Canada
2011 Faculty Lectureship, University of Coimbra, Coimbra, Portugal
2011 Department of Biochemistry and the Cancer Center McGill University,
Montreal, Canada
2011 NCI Tumor Microenvironment Network Meeting Bethesda, MD
2011 Mount Sinai School of Medicine, New York, NY
2011 Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, MA
2011 Banbury Meeting on “Curing Melanoma and Others Cancers”, New York
Future Invited Lectures (Accepted Only)
– March 30-April 1 FCVRI Seminar Series Northwestern University, Chicago
– April 8-12 World Congress of Nephrology, Vancouver
– April 11 OHRI Seminar Series Ottawa
– April 14-16 Extracellular Matrix in Health and Disease A symposium
honoring Bjorn R. Olsen HMS, Boston -April 26-30 Biology of Cancer:
Microenvironment, Metastasis & Therapeutics Meeting Cold Spring Harbor
Laboratory, Cold Spring Harbor NY
– May 11-12 TMEN’s Jr. Investigator Meeting, Boston
– May 18-20 Meeting for the Swedish Society of Pathology and the Swedish
Society of Clinical Cytology Umea, Sweden
– May 20-21 Seminar at Tsinghua, University in Beijing Beijing, China
– May 24-28 CSH Asia Conference on Translational Approaches to Cancer
Suzhou, China
– May 26-27 ICC on Metastasis and Angiogenesis Barcelona, Spain
– June 2-3 32th Annual Meeting ofthe Japanese Society of Inflammation and
Regeneration Kyoto, Japan
– June 25-28 MRS New Concepts in Cancer Metastasis Meeting, Champalimaud
Cancer Centre, Lisbon
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– June30-July 1 20th Annual Meeting of the Japanese Association for Metastasis Research Japan
– July 18-21 Scientific Sessions, BCVS Conference 2011 New Orleans, Louisiana
– August 21-26 Angiogenesis Gordon Research Conference Salve Regina
University, Newport RI
– September 13-16 Mechanisms of Organ Repair and Regeneration Conference
Washington DC
– October 10-13 EMT Meeting in Singapore
– January 16-21 Keystone Symposia Snowbird, Utah
– February, 17-22, Keystone Meeting on Angiogenesis
89
RESEARCH SUMMARY
David Lyden M.D., Ph.D.
Champalimaud Metastasis Programme at
Weill Cornell Medical College
Group members
Jeffrey Greenfield MD/PhD (Assistant Professor/Neurosurgery)
Hector Peinado PhD (Champalimaud Foundation Instructor)
Marianna Papaspyridonos PhD (Fulbright Foundation Post-Doc)
Bethan Psaila MD (Fulbright Foundation Fellow)
Helene Brazier PhD (Department of Defense Post-Doc)
Till-Martin Theilen MD (Post-Doc)
Yujie Huang PhD (Post-Doc)
Haiying Yhang (Post-Doc)
Irina Matei (Post-Doc)
Irini Bournazou (Post-Doc)
Ayuko Nitadori (Japanese Society for the Promotion of Science Post-Doc)
Guillermo Garcia Santos (Clarin Ayudas Post-Doc, Principality of Asturias)
William Cob MD, PhD (Neuro-Surgical Fellow)
Maureen McEvoy MD (Pediatric Surgical Fellow)
Simon Lavotshkin MD (General Surgical Fellow)
Rosario Andre MD (American Portuguese Biomed. Res. Fund/Champalimaud
Foundation PhD student)
Jared Wels (PhD student)
Selena Granitto (PhD student)
Marta Hegueta (Visiting PhD scholar-Spanish Ministry of Science and
Innovation)
Bruno de Costa Silva (Visiting PhD scholar-Ludwig Cancer Institute,
and will be Manning Fd. Post-Doc)
Sumejja Baljevic (Visiting master’s student)
Xueying Chen (Weill Cornell medical student)
Vijay ramaswav (Weill Cornell medical student)
Scott Kerns (Lab Manager)
Caitlin Williams (technician)
90
Overall Summary
Our laboratory investigates the cellular and molecular pathways that
contribute to the tumor and metastatic microenvironments. In response
to tumor-derived secreted factors, we have determined that bone marrow-derived stem and progenitor cells initiate neovasculogeneis and promote
the formation of the “pre-metastatic niche” at future sites of metastasis
providing a favorable microenvironment for the growth of metastatic tumor
cells. We have determined that key embryonic like molecules such as the
inhibitor of differentiation gene or Id genes and essential extracellular
matrix proteins, such as fibronectin isoforms and matrix metalloproteinases
contribute to the support of the pre-metastatic niche. The release of soluble
cytokines and chemokines is currently recognized as the main mechanism
underlying cell-to-cell communication within the tumor microenvironment
as well as the generation of suitable niches in distant organs. Recently, we
have identified a new pathway of crosstalk between tumor cells and bone
marrow-derived progenitor cells called tumor-derived exosomes. Exosomes
are small vesicles (40-100 nm) derived from the luminal membranes of the
late endosomes/multivesicular bodies (MVB), constitutively released via the
fusion of MVBs with the cell membrane. Exosomes were originally considered
to be inert cellular debris. However, it is now accepted that exosomes
can interact with target cells through specific receptor-ligand interactions.
We have found that tumor-derived exosomes are abundantly secreted in
highly metastatic melanoma models compared to less metastatic or non-metastatic models. Melanoma-derived exosomes induced vascular leakiness
at pre-metastatic sites and promoted bone marrow-derived cell mobilization
enhancing primary tumor growth and metastasis. Tumor-derived exosomes
promoted a pro-vasculogenic phenotype, increasing the expression of ADAM10,
THBS1, VEGFA, and VEGFR2 in BM precursors. Moreover, tumor-derived
exosomes increased c-Kit+Tie2+ and CD105+CD29+ progenitor cell populations
in the BM. We identified Rab1a, Rab5b, Rab7, and Rab27a to be highly expressed
in primary melanoma samples. Rab27a interference decreased exosome
production in melanoma cells preventing mobilization of BM progenitor cells,
tumor growth and metastasis. Finally, we identified a “melanoma signature”
in exosomes isolated from melanoma patients, which consisted of Hsp70,
VLA-4, TYRP2, and Hsp90 and, together with Rab proteins, represents
exosome-specific proteins with prognostic and therapeutic potential.
Circulating exosome-derived proteins are diagnostic markers in
melanoma patients
To analyze the significance of circulating exosome levels in metastatic
disease, we have focused our research on melanoma, a highly metastatic form
of cancer, and analyzed the protein level of exosomes isolated from the blood
plasma of melanoma patients. We found that protein levels were significantly
91
increased in the exosome fraction of plasma isolated from melanoma patients
by 5- to 10-fold compared to controls (Fig.1a, P=0.0099).
We used electron microscopy to verify the purification of exosomes in patient
plasma, which demonstrated the characteristic size (100 nm) and shape of
exosomes. In order to characterize the potential proteins found in melanoma
exosomes, we examined the highly metastatic B16-F10 melanoma cell line
model which produces exosomes that are heterogeneous in shape, with an
average size less than 100 nm in diameter (Fig. 1b). Mass spectrometry of
B16-exosomes led to the identification of proteins related to melanoma Fig. 1a
markers, including tyrosinase-related protein 1, melanoma cell adhesion
protein, heat-shock proteins, and integrin subunits. A subset of these proteins
were in turn analyzed in circulating exosomes isolated from melanoma
patients in order to determine their potential as a new diagnostic “signature”
for melanoma patients. We found that tyrosinase-related protein-2 (TYRP2),
a melanoma specific protein, was increased 10-fold in the exosome fraction
of melanoma patients compared to controls (Fig.1c). VLA- 4 (a.k.a, integrin
α4β1 or fibronectin receptor) was upregulated 2-fold (Fig.1c).
We also established that Hsp70 expression increased 7-fold in exosomes
from melanoma patients compared to controls (Fig.1c). In contrast, Hsp90
Fig. 1b
levels were not elevated, suggesting that Hsp90 is a general exosome marker.
Interestingly, we found an Hsp90 isoform in 70% of the melanoma patient
derived exosomes (Fig. 1c arrow), which may indicate the specific shedding
of Hsp90 isoforms in exosomes derived from melanoma patients.
Tumor-released exosomes reach metastatic organs
Analysis of the exosome release rate in culture demonstrated that highly Fig. 1c
malignant cell lines, such as B16-F10, SK-Mel28, and SK-Mel202, secrete
exosomes at much higher levels (from 2-fold to 15-20-fold) than less metastatic
cell lines, such as B16-F1 (Fig. 2a). In contrast, non-tumorigenic and
non-metastatic cells, such as melan-a, secreted very low levels of exosomes
(Fig. 2a). We further confirmed that other tumor cell types, such as breast
and colon cancer cells, secrete tumor-derived exosomes, but at about 2-fold
lower levels than B16-Tail vein-injected B16-F10 exosomes in naïve mice
circulate systemically within blood vessels and arrived within minutes at
organs that eventually served as metastatic sites, such as the lungs and BM.
The arrival of tumor-derived exosomes in the lungs was confirmed with
fluorescently labeled exosomes and staining for CD31 after five minutes
(Fig. 2b). After 24 hours, we found B16 exosomes in the interstitium of the Fig. 2a
Fig. 2b
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lung and in the BM (Fig. 2b), liver, and spleen. All of these organs are common
sites of metastases in melanoma. Vascular leakiness in the lungs is one of
the main factors involved in pre-metastatic niche formation and metastasis.
To analyze the influence of tumor exosomes in endothelial leakiness,
we injected B16 exosomes followed by perfusion 24 hours later with
fluorescently-labeled dextran (MW=70kDa). We demonstrated that B16
exosomes increase lung endothelial permeability after 24 hours, as judged
by the presence of labeled dextran throughout the lung interstitum, when
compared to conditioned media, controls (Fig. 2c) and exosomes from
non-metastatic cell lines.
Fig. 2c
To investigate the molecular pathways in the lungs affected by exosome
delivery, we performed a gene expression profiling microarray of lung
tissue 24 and 48 hours after B16-F10 exosome tail vein injection. We found
a total of 130 genes were differentially expressed; analysis of these genes
demonstrated the upregulation of pathways related to ECM remodeling
and tissue inflammation, such as the family of heat-shock proteins and
S100a9, indicating enhanced expression of previously described effectors
of the pre-metastatic niche. We validated that both S100a9 and S100a8 were
upregulated in the lungs after exosome injection. TNF-α expression was
also upregulated only 24 hours after injection, indicating that TNF-α could
be responsible for the observed increase in vascular permeability.
RESEARCH FUNDING
I)Susan G. Komen for the Cure
“The prognostic and therapeutic implications of bone marrow-derived
progenitor cells in breast cancer invasion and metastasis”
9/1/08-8/31/11
David Lyden PI
II)The Hartwell Foundation
“The role of stroma and microvesicles in recurrent pediatric brain tumor
models”
7/1/09-6/30/12
David Lyden PI
93
I II)D epartment of Defense, Breast Cancer Division
“Unraveling the implication of the hematopoietic stem cells in bone
metastasis of breast cancer.”
1/1/11-2/1/14
David Lyden PI
I V)Manning Foundation
“The role of bone marrow-derived cells in cardiac valvular genesis”
7/1/11-8-1-14
David Lyden PI
V)Malcolm Hewitt Wiener Foundation
“The role of exosome-derived genomic transfer”
4/1/11-5-1-14
David PI
V I)Beth C. Tortolani Foundation
“The molecular signature of inflammatory breast cancer”
6/1/11-7-1-14
PIs: Lyden-Norton-Hudis-Bromberg-Chiosis
PUBLICATIONS
Refereed Journal Articles
Cross KJ, Bomsztyk BD, Weinstein AL, Teo EH, Spector JA, Lyden D. A
novel method for targeted gene therapy in ischemic tissues through viral
transfection of an expression cassette containing multiple repeats of hypoxia
response element. Plastic and Reconstructive Surgery 2009 123:72-82.
Teo EH, Cross KJ, Bomsztyk ED, Lyden DC, Spector JA. Gene therapy in
skin: choosing the optimal viral vector. Ann Plast Surg 2009 62(5): 576-580.
Psaila B, Lyden D. “The metastatic niche: adapting the foreign soil”
Nature Reviews Cancer 2009 9:285-293.
Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C,
MacDonald DD, Jin DK, Shido K, Kerns SA, Zhu Z, Hicklin D, Wu Y, Port
JL, Altorki N, Port ER, Ruggero D, Shmelkov SV, Jensen KK, Rafii S, Lyden
D, Wels J (corresponding author). VEGFR1 knock-down in myelomonocytic
cells eradicates tumour seeding and metastasis in a non-amputation tumour
model. Nature 2009 461:E5-E6.
94
Chan AS, Jensen KK, Skokos D, Doty S, Lederman HK, Kaplan RN, Rafii
S, Rivella S, Lyden D. Id1 represses osteoclast-dependent transcription and
affects haematopoiesis and bone formation. PLoS One 2009 4(11): 1-14.
Podolanczuk A, Psaila B, Lyden D. “Role of Bone Microenvironment/
Metastatic Niche in Cancer Progression” in Bone and Cancer. Springer-Verlag Press. 2009. Chapter 6, 89-101.
James D, Nam H, Seandel M, Nolan D, Janovitz T, Tomishima M, Studer L,
Lyden D, Benezra R, Zaninovic N, Rosenwaks Z, Rabbany SY, and Rafii S.
Expansion and maintenance of human embryonic stem cellderived endothelial
cells by TGFB inhibitions Id1. Nature Biotechnology 2010 28(2):161-166.
Greenfield JP, Cobb WS, Lyden D. Resisting arrest: A switch from angio-genesis to vasculogenesis in recurrent malignant gliomas. Journal of
Clinical Investigation 2010 120(3):663-667
Dunkel IJ, Khakoo Y, Kernan NA, Gershon T, Gilheeney S, Lyden DC, Wolden
SL, Orjuela M, Gardner SL, Abramson DH. Intensive multimodality therapy
for patients with stage 4a metastatic retinoblastoma. Pediatric Blood and
Cancer, 2010 55(5):55-59.
Ding B, Nolan DJ, Butler JM, James D, Babazadeh A, Rosenwaks Z, Mittal
V, Kobayashi H, Shido K, Lyden D, Sato TN, Rabbany SY, Rafii S. Inductive
angiocrine signals from sinusoidal endothelium are required for liver
regeneration. Nature, 2010 468:310-315.
Acharya SS, Kaplan RN, MacDonald D, Fabiyi OT, DiMichele D, Lyden D.
Neo-angiogenesis contributes to the development of hemophilic synovitis.
Blood, 2011 117(8):2484-2493.
Peinado H, Lavtoshkin S, Lyden D. “The secreted factors responsible for
pre-metastatic niche formation: Old sayings and new thoughts” Semin
Cancer Biol. 2011 21(2):139-146.
Peinado H, Lavothskin S, Costa da Silva B, Moreno-Bueno G, Chapman PB,
Bromberg JF, Lyden D. Tumorderived exosomes educate bone marrow
progenitor cells leading to a pro-angiogenic and pro-metastatic behavior.
Nature Medicine, In Review.
95
Meetings Organized
5th International Symposium on Translational Oncology
University of Barcelona
Barcelona, Spain
March 2009
Co-organizer
Metastasis Summer School Meeting
European Union Task Force, TuMIC
Sesimbra, Portugal
September 2009
Co-organizer
Global Meeting of Translational Science
A.C. Carmago Hospital
Sao Paolo, Brazil
Organizing Committee Member
New Concepts in Cancer Metastasis
TuMIC/European Union
Lisbon, Portugal
June 2011
Organizing Committee Member
Invited presentations
Invited Speaker
“The metastatic niche: Adapting the foreign soil”
Kaplan RN, Wels J, Lyden D
Mechanisms of migration, invasion and metastasis
Beatson Cancer Institute/University of Glasgow
Glasgow, Scotland
July 2009
Keynote Speaker
“Priming the soil for metastasis”
Kaplan RN, Theilen T, Wels J, Lyden D
Progenitor Cells, Microenvironment and Cell Fusion in Cancer Progression
Swedish Research Council
Stockholm, Sweden
October 2009
96
Invited Speaker
“The metastatic niche: Adapting the foreign soil”
Kaplan RN, Theilen T, Wels J, Peinado H, Lyden D
5th International Conference on Tumor Microenvironment/AACR
Progression, Therapy and Prevention
Versailles, France
October 2009
Opening Address-Keynote Speaker
“The metastatic niche” Adapting the Foreign Soil”
Lyden D
IX Symposium on Extracellular Matrix
Buzios, Brazil
November 2009
Medical Grand Rounds Speaker
“The contribution of bone marrow-derived cells in metastatic progression”
Kaplan RN, Lyden D
A. C. Carmago Cancer Center
Sao Paolo, Brazil
November 2009
Inaugural Address-Keynote Speaker
“The contribution of bone marrow-derived cells in metastatic progression”
Kaplan RN, Lyden D
Official opening of the University of Sao Paolo Cancer Center
Sao Paolo, Brazil
November 2009
Invited Speaker
“The pre-metastatic niche: Adapting the foreign soil”
Kaplan RN, Lyden D
Molecular Targets and Cancer Therapeutics: Discovery, Biology and Clinical
Applications
AACR
Boston, Mass.
November 2009
Featured Speaker (Introduced by Joan Massague)
“The role of microvesicles in metastatic progression”
Peinado H, Lavotshkin S, Lyden D
Metastasis Theme for Translational Research at Memorial Sloan-Kettering
Cancer Center
New York, NY.
December 2009
97
Keynote Speaker
“Priming the soil: The pre-metastatic niche”
Kaplan RN, Lyden D
Irish Association for Cancer Research
Galway, Ireland
March 2010
Keynote Speaker
“Priming the soil for the pre-metastatic niche”
Lyden D
Belgium Society of Cell Biology and Development/European Union Task
Force on Metastasis
Liege, Belgium
March 2010
Invited Speaker/Session Chair (Dr. James Watson)
Tumor Microenvironment and Metastasis
The Banbury Center, Cold Spring Harbor Laboratory
Cold Spring Harbor, New York
May 2010
Invited Speaker
NCI Tumor Microenvironment Network/Junior Investigator Meeting
New York, New York
May 2010
Master of Ceremony/Speaker
Dinner/Conference honoring Dr. Mina Bissell
Berkeley, California
May 2010
Invited Speaker
NCI-The Molecular Bases of Radiation Resistance of Human Cancers
Bethesda, Maryland
September 2010
Plenary Session Chairperson
The Influence of the Niche
Metastasis and The Tumor Microenvironment
AACR/Metastasis Research Society
Philadelphia, Pennsylvania
September 2010
98
Keynote Speaker
National Spanish Oncology Meeting
Salamanca, Spain
November 2010
Honored Lecturer
MD Anderson Cancer Center
Houston, Texas
February 2011
Session Chair/Speaker
Keystone Symposia on Stem Cells, Cancer and Metastasis
Keystone, Colorado
March 2011
Educational Committee Chairman
AACR
“Emerging Role of Exosomes in Cancer Invasion and Metastasis”
Orlando, FL
April 2011
Visiting Lecturer/Organizer
StratCan Summer School (on metastasis) for Post-Doctoral Fellows
Karolinska Institutet
Stockholm, Sweden
June 2011
Keynote Speaker
11th Annual Immunology Conference
Roswell Park Cancer Institute
Buffalo, New York
September 2011
Invited Speaker
The Tumor-Vessel Interface
Kloster Seeon Meeting
Munich, Germany
September 2011
Grand Rounds Speaker
Tulane Univ. Cancer Center
New Orleans, La.
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5 PRÉMIO ANTÓNIO CHAMPALIMAUD
DE VISÃO
5.1 Reunião do Júri e selecção dos premiados
5.2 Cerimónia de atribuição do Prémio
5.3 Preparação do Prémio 2011
5.4 Conferência do Prémio António Champalimaud de Visão na ARVO
5.5 ARVO Foundation Host-a-Researcher Programme
5 PRÉMIO ANTÓNIO
CHAMPALIMAUD DE VISÃO
Os premiados, Dr. Movshon
e Dr. Newsome
O Prémio visa estimular o que de melhor se faz no campo da ciência biomédica, apoiando, ao mesmo tempo, a transferência do conhecimento actual
para o terreno onde as descobertas cientificas devem ser aplicadas naqueles
que mais precisam. É com este modelo que o Prémio se tem afirmado
internacionalmente.
A Fundação já entregou o Prémio por quatro vezes: duas reconhecendo esforços extraordinários na prestação de cuidados de saúde em oftalmologia às
populações nos países em desenvolvimento, como é o caso do Aravind Eye
Care System, em 2007 e da Helen Keller International, em 2009 e outras duas reconhecendo investigação médica fundamental para o conhecimento e compre-
ensão dos mecanismos da visão, aos laboratórios do Dr. Nathans e do Dr. Yau,
em 2008, e aos laboratórios do Dr. Movshon e do Dr. Newsome, em 2010.
No contexto do Prémio, a Fundação estabeleceu importantes parcerias com
organizações internacionais e com a comunidade científica, que tiveram como
resultado um aumento da nossa rede de contactos, bem como um alargado
reconhecimento internacional. A presença de representantes da Fundação em
várias conferências e encontros veio a traduzir-se num maior conhecimento
sobre os objectivos do Prémio e do nosso trabalho em geral. O reforço e o
alargamento destas iniciativas e a expansão da nossa rede de “nomeadores”
continuam a desenvolver-se.
101
5.1Reunião do Júri e selecção dos premiados
Em Junho de 2010, o painel do Júri reuniu para seleccionar o premiado e
completar o complexo processo de selecção.
O Prémio António Champalimaud de Visão contemplou o trabalho realizado
nos últimos trinta anos por Anthony Movshon e William Newsome. Estes dois
cientistas trabalharam juntos e individualmente em descobertas excepcionais
sobre a forma como o cérebro reconstrói imagens, de maneira que os seres
humanos possam apreender, interpretar e actuar no mundo. Ao construir, por
um lado, uma ponte entre a psicofísica e o comportamento humano e, por
outro lado, uma ligação entre a fisiologia dos neurónios individuais e aquilo que
eles processam, estes dois cientistas conseguiram explicar a maneira como o
cérebro reconstrói imagens visuais.
Leonor Beleza afirmou a propósito deste prémio: “a percepção visual começa
nos olhos, mas é compreendida no cérebro. Durante um período de 30 anos,
o trabalho do Dr. Movshon e do Dr. Newsome levou este axioma para novos
níveis de compreensão científica. Devido a estes dois neurocientistas, temos
agora uma compreensão fundamental para o papel dos neurónios na forma
como vemos as coisas que se movem no mundo. O seu trabalho inovador, em
conjunto e individualmente, criou as bases para a pesquisa continuada sobre
como o cérebro processa a visão. Estamos, pois, muito orgulhosos com a
escolha do júri”.
Em estudos anteriores, o Dr. Movshon contribuiu para a compreensão sobre
a maneira como o cérebro representa a forma e o movimento dos objectos,
identificando, pela primeira vez, o processo de percepção de movimento que
ocorre nos circuitos neurais no lobo temporal médio do cérebro. Num estudo
conjunto realizado em 1989, que é hoje considerado um estudo clássico, os
cientistas demonstraram que os neurónios na região do lobo temporal médio
da área de visão são responsáveis pelos julgamentos da percepção sobre a
102
orientação. Ao monitorizar as respostas dos neurónios, conseguiram prever,
com acuidade, as decisões sobre a percepção, ligando assim a percepção
a padrões de actividade específicos nos circuitos neurais. O Dr. Newsome
demonstrou que, alterando especificamente a actividade nestes neurónios, o
desempenho da percepção poderia ser melhorado ou diminuído.
Estes estudos provaram que a actividade dos neurónios no lobo temporal médio
do cérebro é necessária para que os seres humanos possam ver objectos no
mundo. Demonstrando inequivocamente este facto, os Doutores Movshon e Membros do Júri do Prémio
Newsome prepararam o caminho para estudos sobre os processos mentais que
António Champalimaud de Visão
ligam a percepção à acção e para um maior entendimento sobre os complexos
processos que estão na base da tomada de decisões e do comportamento
humano.
5.2Cerimónia de atribuição do Prémio
Desta vez a cerimónia de entrega do Prémio não teve lugar no Mosteiro dos
Jerónimos, como em anos anteriores, mas sim no Champalimaud Centre for
the Unknown e durante a respectiva inauguração. Foi precedida por uma intervenção do Professor António Damásio, curador da Fundação Champalimaud
e Presidente do Brain and Creativity Institute da Universidade da Califórnia do
Sul, que falou sobre o extraordinário trabalho dos premiados, e introduzida pela
Presidente da Fundação Champalimaud, Dra. Leonor Beleza.
Os premiados com o Presidente
do Júri, Prof. Alfred Sommer
e o Conselho de Administração
5.3Preparação do Prémio de 2011
A preparação do Prémio 2011 teve início em 2010 e traduziu-se em múltiplos
esforços para atrair uma vasta selecção de nomeações, incluindo uma nova
edição da brochura com a regulamentação do Prémio para 2011, bem como a
expansão da rede de “nomeadores”.
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5.4Conferência do Prémio António
Champalimaud de Visão na ARVO
Em colaboração com a Association for Research in Vision and Ophthalmology
(ARVO), a Fundação organizou, no dia 5 de Maio, e pela terceira vez, uma
conferência e recepção, no âmbito da reunião anual da ARVO, no Centro de
Convenção de Fort Lauderdale, nos E.U.A.
A terceira conferência ARVO/Champalimaud Vision Award Lecture foi proferida por Kathy Spahn, Presidente e CEO da Helen Keller International (HKI),
instituição galardoada com o Prémio António Champalimaud de Visão em 2009
pelos seus programas em vários países do mundo, no combate à malnutrição,
cataratas, tracoma, cegueira dos rios, entre outros. A HKI foi particularmente
instrumental na criação de programas de controlo da deficiência de vitamina A
em crianças, e oferece actualmente estes programas em treze países africanos
e cinco países asiáticos. A HKI ajuda a salvar a visão de milhares de crianças,
anualmente.
A Fundação Champalimaud esteve representada pelo Professor António Borges
membro da Administração. Elogiando a contribuição da HKI a nível mundial,
afirmou “A filantropia continuará a alargar-se, porque cada vez mais pessoas
procuram formas de aplicar a sua responsabilidade social e financeira na
nossa sociedade, procurando devolver a essa mesma sociedade, pelo menos,
uma parte daquilo que a sociedade lhes deu. Para essas instituições e para
esses generosos indivíduos, o principal desafio está em como aplicar bem o
seu dinheiro. É por isso que a Helen Keller International é tão importante para
nós. Provam que isso pode ser feito; que o dinheiro será bem utilizado; que
os resultados serão tangíveis e que terão um impacto alargado em milhões Prof. António Borges, membro
Conselho de Administração
de pessoas. É o seu sucesso, o seu mérito, a sua dedicação focalizada que do
alimenta a filantropia, motiva os doadores e nos ajuda a construir um mundo discursando na conferência da ARVO
melhor”.
A ARVO – The Association for Research in Vision and Ophthalmology é a maior
organização mundial na área da visão, com mais de 12.000 membros em 73
países. A conferência ARVO/Champalimaud Lecture marca a continuação
da forte ligação entre a Fundação Champalimaud e a ARVO, que teve início
em 2006 quando o Prémio de Visão foi, pela primeira vez, apresentado pelo
então Presidente desta associação, Larry Takamoto.
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5.5ARVO Foundation Host-a-Researcher
Programme
A Fundação Champalimaud apoia o Host-a-Researcher programme da ARVO
Foundation for Eye Research (AFER), agora denominado Developing Country
Eye Researcher Fellowship. O programa desenvolvido em colaboração com a
AFER, focaliza-se na identificação de participantes provenientes de países em
desenvolvimento e no estimulo ao contacto e colaboração com cientistas e
organizações que estão presentes na Conferência anual da ARVO. Além do
apoio e acompanhamento do programa, a Fundação Champalimaud tem tido Trabalho da Fred Hollows Foundation
um papel fundamental na identificação de estudantes, investigadores e/ou
New Zealand em Timor Leste
médicos na área da oftalmologia de países de expressão portuguesa.
A partir deste programa, os participantes em anos anteriores têm desenvolvido colaborações estreitas com resultados significativos, quer do ponto
vista científico, quer com acções no terreno. Um bom exemplo é o trabalho
desenvolvido por um participante da Fred Hollows Foundation New Zealand,
em Timor Leste, em colaboração com a Harvard Medical School e o Tilganga
Eye Center no Nepal.
Membros do Programa Developing
Country Eye Researcher Fellowship
na Conferência da ARVO em 2010
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6 REDE C-TRACER
6.1 C-TRACER – Índia
6.2 C- TRACER – Portugal
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6 C-TRACER
C-TRACER - Índia
6.1C-TRACER - Índia
Em 2010, o C-TRACER – Champalimaud Translational Centre for Eye Research
– entrou no seu terceiro ano de existência. O centro, oficialmente inaugurado
em Hyderabad, Índia, em 30 de Janeiro de 2008, foi criado a partir de
uma parceria histórica entre a Fundação Champalimaud e o LV Prasad Eye
Institute (LVPEI). O C-TRACER está focalizado na utilização de técnicas muito
avançadas com células estaminais, contrinuindo para soluções inovadoras
para o tratamento das doenças da visão. Em particular, a equipa de cientistas
do C-TRACER tem efectuado investigação nas áreas da genética molecular e
da genética funcional das doenças da visão (cataratas, glaucoma, distrofias
da córnea e doenças da retina), na área da biologia celular com especial
ênfase na utilização de células estaminais para tratamento de problemas
de visão, na microbiologia e na bioquímica. É especialmente importante o
trabalho de actividade translacional de aplicação dos resultados laborato-
riais no tratamento e terapias aplicadas a doentes.
O campo de actuação da biologia celular e terapia C-TRACER situa-se em
três áreas principais:
–Transplante de epitélio límbico de cultura (CLET), que se tornou num Prof. Gullapalli Rao membro fundador
modelo standard no tratamento de patologias da córnea em pacientes que do LV Prassad Eye Institute (LVPEI)
e membro do Júri do Prémio António
sofreram de acidentes com químicos ou fogo. Até à data, mais de 700 Champalimaud de Visão
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tratamentos deste tipo foram completados, 42 dos quais em 2010, e foram
analisados os resultados em mais de 405 pacientes. Estes resultados serão,
em breve, publicados, e foram apresentados na 2010 Gordon Research
Conference em Ventura, EUA, e na conferência da ARVO em 2010 em Fort
Lauderdale, EUA. A aplicação do processo CLET torna este trabalho num dos
maiores casos de sucesso na utilização de terapia com células estaminais
adultas, a nível mundial.
–Quando este processo de transplante de epitélio límbico de cultura não é
possível, a equipa do C-TRACER desenvolveu um tratamento alternativo com
base no transplante de tecido da mucosa oral, cultivadas da mesma forma
que no procedimento com células límbicas, e transplantados já em mais de
30 pacientes. Alguns destes caso responderam muito bem, enquanto outros
estão ainda a ser estudados.
–Preparação de Células Estaminais Pluripotentes induzidas (iPSCs induced
Pluripotent Stem Cells): ao desenvolver a teoria de que as células estaminais
podem ser geradas a partir de outras células do corpo, através da introdução
de genes específicos (ou factores proteicos), a equipa do C-TRACER iniciou
uma produção destas iPSCs, de forma a estudar e corrigir células em pacientes
com formas de patologia de retinite pigmentar. Sendo este um projecto de
longo curso, que poderá levar alguns anos, a equipa já conseguiu produzir
iPSCs de ratinhos e transferi-los para humanos.
Prof. Balasubramanian,
Director C-TRACER - Índia
Durante 2010, o C-TRACER continuou a aumentar a sua reputação como
um dos centros mundiais lideres na investigação em células estaminais.
Dirigido pelo Professor Balasubramanian, um dos investigadores indianos
de maior reputação e ex-Presidente da Academia de Ciências da Índia, a
equipa continuou o desenvolvimento dos seus tratamentos revolucionários
com células estaminais, bem como a sua dedicação a outros projectos
muito inovadores. Estes incluem genética funcional induzida e genética do
glaucoma. O seu trabalho continua a produzir resultados excepcionais que
foram publicados em 15 artigos do sector científico durante 2010.
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Cerimónia de inauguração
C-TRACER - Portugal,
6 de Outubro de 2010
6.2C- TRACER – Portugal
Foi celebrado um acordo entre a Fundação Champalimaud e a AIBILI – Associação para Investigação Biomédica e Inovação em Luz e Imagem, sediada em
Coimbra, com o objectivo de estreitar a colaboração entre ambas as instituições e de atribuir à AIBILI a qualificação de C-TRACER, à semelhança do
existente em Hyderabad, na Índia. É particularmente importante a possibilidade de intercâmbio de investigadores entre a Índia e Portugal.
Este acordo foi oficialmente anunciado no dia 6 de Outubro, com a presença
do Prof. José Cunha Vaz, Presidente do AIBILI e membro do Júri do Prémio
António Champalimaud de Visão, da Presidente da Fundação Champalimaud,
Dra. Leonor Beleza e do Dr. João Silveira Botelho, bem como do Prof. Gullapalli
Rao, membro do Júri do Prémio e fundador do LV Prasad Institute e do
Prof. Balasubramanian, Director do C-TRACER – Índia.
A AIBILI foi constituída em 1989 com o objectivo de apoiar a transferência de
tecnologia para a indústria da Saúde e é hoje reconhecida a nível nacional
e internacional como instituição de referência em investigação na área das
ciências da visão.
A AIBILI tem capacidades de infra-estrutura central para a coordenação de
investigação clínica de iniciativa do investigador, sendo o centro coordenador da Rede Europeia de Centros de Ensaios em Oftalmologia (EVICR.net
- European Vision Institute Clinical Research Network), composta por 71
Centros de Ensaios Clínicos em Oftalmologia de 16 países da União Europeia.
Leonor Beleza na abertura
do C-TRACER - Portugal
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7 OUTRAS PARCERIAS
7 OUTRAS PARCERIAS
Foi continuada em 2010 a participação activa da Fundação Champalimaud
nas actividades do Health Cluster Portugal (HCP), que é o primeiro “Pólo de
Competitividade e Tecnologia” lançado em Portugal, sendo a Dra. Leonor
Beleza a presidente do seu Conselho Fiscal.
O HCP tem prosseguido o seu objectivo de transformar o nosso país num
player competitivo na área da saúde, juntando “o que de melhor existe em
Portugal na cadeia de valor da saúde”, contando já com mais de uma centena
de associados (106 em 2010) que representam mais de 70% dos doutorados
a trabalhar em Portugal para o sector da saúde e, na área clínica, mais
de 20% das camas e dos médicos do país.
Em 2010 foi criada a Comissão de Adesão, para promover o processo de
angariação e de selecção dos novos associados.
A Assembleia-Geral do HCP reuniu duas vezes em 2010, sendo a de Março
seguida de uma reunião de associados sobre o tema “As patentes na criação
de valor na área da saúde”, e coincidindo a de Dezembro com a celebração
da I Conferência Anual do HCP, subordinada aos temas “Sustentabilidade e
Competitividade na Saúde” e “Evolução dos modelos de negócio no mercado
da Saúde”.
O programa de acção do HCP está estruturado em Projectos-Âncora,
Projectos-Bandeira e Outros Projectos, sendo que o Centro de Investigação
Champalimaud é um dos seus Projectos-Bandeira.
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8 PROGRAMA CHAMPIMÓVEL
8.1 Introdução
8.2 Objectivos
8.3 Protocolos
8.4 Eventos
8.5 Roteiro
8.6 Sessões e visitas
8.7 Reuniões
8.8 Divulgação
8 PROGRAMA CHAMPIMOVEL O Champimóvel na Expo
8.1Introdução
A Fundação Champalimaud acredita que o futuro da investigação científica
em Portugal passa pela motivação dos jovens para a ciência.
A Fundação quer contribuir activamente para a promoção do conhecimento
científico e para atrair as novas gerações para a ciência e para a investigação,
e foi neste contexto que criou o Champimóvel.
Em 2008 teve início a acção Champimóvel, que é um simulador transportável
em que é exibido um filme animado interactivo sobre o funcionamento do
corpo humano, apresentado por um boneco de animação – o Champi.
Desloca-se ao encontro do seu publico-alvo, por forma a garantia um acesso
generalizado.
8.2Objectivos
A Fundação Champalimaud pretende que o Champimóvel percorra as escolas
de todo o país, com o objectivo de despertar a curiosidade dos estudantes do
2º e 3º ciclo para a ciência e para a investigação científica.
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A acção tem como objectivos:
– despertar o interesse dos jovens estudantes pelos temas científicos e
incentivar talentos nessa área;
– envolver activamente alunos e professores na acção, através de um conjunto
de actividades que ultrapassem a apresentação do espectáculo, de maneira
a manter o interesse dos jovens pela ciência.
É um espectáculo animado interactivo em 4D com cerca de 25 minutos: uma
viagem através do corpo humano, apresentada pela personagem Champi.
Este começa por explicar o mecanismo da visão, seguido da apresentação
da célula e do seu material genético, da acção dos vírus, da terapia
genética e finalmente das investigações recentes em células estaminais e
nanotecnologias.
8.3Protocolos
A Fundação Champalimaud estabeleceu um protocolo com o Ministério da
Educação (ME), através da Direcção Geral de Investigação e Desenvolvimento Curricular (DGIDC).
A Fundação conta assim com o apoio das Direcções Regionais de Educação
no contacto e envolvimento das escolas.
A equipa do Champimóvel, actua em estreita colaboração com a Direcção
Regional de Educação (DRE) e estabelece os contactos com as autoridades
locais (Câmaras Municipais), para identificação do local de realização da
acção e algum apoio.
O Champimóvel na Castanheira
É da responsabilidade da Direcção Regional de Educação (DRE) efectuar os
primeiros contactos com os órgãos executivos das escolas para convidar à
sua participação nas datas previstas em roteiro.
Contamos também com o seu apoio na transmissão do programa da acção
e requisitos de segurança, que deverão ser do conhecimento da escola,
professores e alunos.
8.4Eventos
Realizaram-se 23 eventos (mais nove do que em 2009 e mais vinte do que
em 2008), nos seguintes locais e instituições:
Vila Nova da Barquinha – Parque do Município Fundação LIGA
Taça de Portugal de Futebol Feminino no Estádio do Jamor
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Parque da Cidade de Loures
Tagus Park
Feira do Livro de Leiria
Batalha (Feira do Artesanato)
Caldas da Rainha
Salvaterra de Magos (Festas da Cidade)
Pombal (Festas do Bodo)
Dia Mundial da Criança e do Ambiente na Sertã
Mação (Festas da Cidade)
Ansião (Festas da Cidade)
Parque da Cidade de Torres Vedras
SIVA (Open Day)
Portas Abertas 2010 (Grupo Luís Simões)
Optimus Alive! 2010 (parceria com o Instituto Gulbenkian de Ciência, em Algés)
Tábua XXI
Ourém (Prémio Eco Escolas)
Paços de Ferreira (Verão Aberto)
Centenário da Implantação da Republica
Autódromo do Estoril (Ciência e Desporto)
Universidade do Minho (Semana da Ciência e da Tecnologia)
Em 2010 o Champimóvel esteve aberto ao público em geral nos centros de
Ciência Viva de Proença-a-Nova e no Pavilhão do Conhecimento.
8.5Roteiro
O roteiro do Champimóvel vai sendo definido em articulação com o Ministério O Champimóvel em Montalegre
da Educação e conforme diversos critérios.
Fora dos períodos escolares são programadas outras visitas, como centros
de Ciência Viva, Câmaras Municipais, hospitais e outras instituições, eventos
esses aberto ao público em geral. O sucesso do Champimóvel também se manifesta através de um maior
número de pedidos de visitas
Durante o ano de 2010, o Champimóvel esteve em 7 distritos - Santarém,
Leiria, Porto, Coimbra, Lisboa, Castelo Branco e Braga (mais 2 distritos do
que em 2009 e mais 3 distritos do que em 2008)-, percorreu 54 concelhos,
nomeadamente 4 concelhos do distrito de Setúbal, 14 concelhos do distrito de
Santarém, 16 concelhos do distrito de Leiria, 1 concelho do Porto, 1 concelho
do distrito de Braga, 6 concelhos do distrito de Lisboa e 11 concelhos do
distrito de Castelo Branco (mais 22 concelhos do que em 2009 e mais 33
concelhos do que em 2008), 181 escolas (mais 68 escolas do que no ano de
2009 e mais 141 do que no ano de 2008).
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Em 2010 o Champimóvel percorreu 8140 kms (mais 1390 kms do que no ano
de 2009 e mais 2914 Kms do que em 2008).
8.6Sessões e visitas
Durante o ano de 2010 realizaram se 1421 sessões (mais 62 do que em 2009
e mais 513 do que no ano de 2008), perfazendo um total de 31192 visitas
(mais 6527 visitantes do que em 2009 e mais 16140 visitantes do que no ano
de 2008), sendo 26427 dos visitantes crianças (mais 5887 crianças do que
em 2009 e mais 13025 crianças do que em 2008), 2010 professores (mais
21 professores do que em 2009 e mais 1340 professores do que no ano de
2008) e 2775 adultos/não docentes (mais 619 do que em 2009 e mais 1775
do que em 2008).
8.7Reuniões
Em 2010 houve 79 reuniões em Câmaras Municipais (mais 38 reuniões
do que no ano 2009 e mais 71 reuniões do que em 2008), reuniões essas
preparatórias para receberem o Champimóvel nos seus municípios. Para além
de um membro do executivo camarário, está também presente o director do
agrupamento escolar, alguns professores e um representante da Direcção
Regional de Educação da respectiva área.
8.8Divulgação
O roteiro e as actividades relacionadas com o Champimóvel estão disponíveis no site da Fundação Champalimaud (www.fchampalimaud.org) e no
www.parlamentoglobal.pt.
A bordo do Champimóvel
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9.1 Conselho de Curadores
9.2 Conselho Cientifico
Concelho de Admistração
Dra. Leonor Beleza, Dr. João Silveira
Botelho e Prof. António Borges
9.1Conselho de Curadores
Em 2010 foram organizadas duas reuniões do Conselho de Curadores,
a primeira em 11 de Junho e a segunda logo após a inauguração do
Champalimaud Centre for the Unknown, a 6 de Outubro.
9.2Conselho Científico
Em 2010, o Conselho Científico da Fundação Champalimaud continou a
prestar a sua prestigiosa colaboração e orientação relativamente às nossas
actividades. Neste contexto, a reunião anual teve lugar no dia 4 de Outubro
com a presença de James Watson, Presidente do Conselho, de Alan
Ashworth (Breakthrough Breast Cancer Research Centre, Reino Unido),
Mark Bear (Massachusetts Institute of Technology, EUA), Ronald Blasberg
(MSKCC – Memorial Sloan-Kettering Cancer Centre, EUA), Barry Dickson
(Institute of Molecular Pathology, Áustria), Paul Marks (MSKCC – Memorial
Sloan-Kettering Cancer Centre, EUA), J. Anthony Movshon (New York
University, EUA), Sir Keith Peters, ( ex-Presidente da Academy of Medical
Sciences, Reino Unido), Martin Raff (University College London, Reino Unido)
e Susumu Tonegawa (Massachusetts Institute of Technology, EUA).
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Os trabalhos da reunião centraram-se, mais uma vez, no desenvolvimento
da investigação em neurociências, bem como na preparação da abertura da
clínica oncológica e respectivo programa de investigação.
Todos os membros assistiram, igualmente, à inauguração do Champalimaud
Centre for the Unknown, que teve lugar a 5 de Outubro de 2010.
A Comissão científica continuará a reunir anualmente, cumprindo a sua função
orientadora dos assuntos científicos e médicos da Fundação.
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10 COMUNICAÇÃO E PATROCÍNIOS
10.1 “730 Dias” num livro
10.2 Fotografias
10.3 Patrocínios
10COMUNICAÇÃO E PATROCÍNIOS
10.1“730 Dias” num livro
A Fundação Champalimaud promoveu a publicação de um livro de fotografias de
Rui Ochôa que retrata o processo de construção do Centro de Investigação.
Esse processo está profusamente documentado em fotografia e em filme, na
verdade desde antes de ter sido iniciado, porque foi recolhido e guardado um
acervo abundante de registos da área da construção.
Todo este material documenta para o futuro o que era o espaço que agora
ocupamos, e como decorreram as obras que conduziram à sua configuração
actual.
Rui Ochôa, foto jornalista de profissão e habitual colaborador da Fundação, Livro 730 Dias, de Rui Ochôa
esteve envolvido desde muito cedo neste esforço de documentação.
O livro corresponde a uma primeira utilização sistematizada do grande acervo
documental de que dispomos.
Chama-se 730 dias, é uma edição bilingue, e conta com uma descrição, pelo
Arquitecto Charles Correa, o autor do projecto, do seu próprio envolvimento.
O título refere-se ao tempo que foi necessário para demolir o que existia antes,
e depois erguer, construir e completar o belíssimo complexo arquitectónico
que constitui um campus. Muito pouco tempo, na verdade, que conduziu do
lançamento da primeira pedra, a 5 de Outubro de 2008, ao término da obra e à
sua inauguração, no dia 5 de Outubro de 2010, um dia histórico em Portugal.
Percorrendo a obra, seguimos a par e passo como foi sendo, e acontecendo,
uma extraordinária transformação de espaço. E nela ficam registados inúmeros
protagonistas anónimos que, todos juntos, contribuíram para que seja uma
realidade o Centro de Investigação Champalimaud.
10.2Fotografias
Para além do que já foi acima referido a propósito do livro 730 dias, a Fundação
tomou a iniciativa, na fase final da construção, de solicitar a 10 fotógrafos
seleccionados que retratassem momentos do processo de construção. Essas
fotografias pertencem hoje também ao acervo da Fundação e estão expostas
em áreas públicas.
Fotografias expostas no foyer
do Auditório da Fundação
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10.3Patrocínios
Exposição: “Arte Médica e Imagem do Corpo. De Hipócrates ao Final do
Século XVII”
Esta exposição foi organizada pela Biblioteca Nacional de Portugal e inaugurada a 7 de Abril, e é representativa do riquíssimo acervo da BNP e da Biblioteca
da Ajuda. Na selecção dos títulos houve a preocupação de evidenciar as
obras de referência, que marcaram dois milénios de história da medicina.
Estiveram em exposição obras das figuras mais eminentes que se ocuparam
da arte médica. Numa sequência que combina a articulação temática e a
progressão histórica, puderam apreciar-se livros da autoria de Hipócrates,
Galeno, Avicena, Averróis, Pedro Hispano, Mondino, Vesálio, Francisco
Sanches, Harvey, Borelli, Boerhaave, Stahl, Ribeiro Sanches e Pinel.
10.4Exposição: “Corpo - Estado, Medicina
e Sociedade no tempo da I República”
Exposição da responsabilidade da Comissão Nacional para as Comemorações do Centenário da República, foi inaugurada a 23 de Julho e esteve
patente ao público até final de Dezembro.
Esta exposição pretendeu dar conta da história da medicina em Portugal
nas décadas da consolidação do prestígio dos médicos, bem como das
relações entre o saber destes, o poder político e os diversos grupos sociais.
A mostra de objectos, documentos e fotografias visou, também, problematizar as relações do médico com o doente e com o corpo humano, individual
ou social, e questionar o saber científico da medicina e dos médicos no tempo
da I República.
A Fundação Champalimaud apoiou a realização destas duas mostras.
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11 GESTÃO DO PATRIMÓNIO FINANCEIRO
123
11GESTÃO DO PATRIMÓNIO FINANCEIRO
1.2010 foi um ano de continuação da recuperação dos mercados financeiros à
escala global. Depois de uma assinalável recuperação em 2009, quase todos
as categorias de activos registaram retornos positivos em 2010. O principal
período de ganhos no ano foi o quarto trimestre, altura em que ficou claro
que as economias continuavam a crescer, afastando receios dum novo
afundamento depois do de 2008. A carteira de investimentos da Fundação
manteve-se integralmente aplicada sem grandes alterações às alocações de
activos anteriores. Os ganhos da Fundação em 2010 foram de 44.779.917€
o que elevou o valor do seu portfólio financeiro para 478.689.765€, a preços
de mercado.
2. É bom recordar que a política de investimento da Fundação se assume passiva,
não se alterando com base em oscilações de curto prazo que se verifiquem
nos mercados financeiros. Uma política mais activa que reaja a variações de
curto prazo comporta altos riscos, incluindo o de vender activos em alturas de
cotações baixas e recomprá-los depois a preços mais altos. A estruturação da
carteira de investimentos da Fundação foi concebida tendo em conta os seus
objectivos de longo prazo que são a maximização de resultados, combinada
com uma adequada diversificação do seu portfólio para reduzir a volatilidade
em termos globais. Essa orientação garante á Fundação a protecção dos
seus capitais em ambientes desfavoráveis (como aconteceu em 2008) mas
também a participação nos ganhos nas conjunturas favoráveis - como nos
dois últimos anos.
3.Como já foi referido em anos anteriores a política geral de investimentos
financeiros da Fundação é de crescimento do seu capital a longo prazo.
Aceitando um nível mais elevado de risco, o que se reflecte na volatilidade
do portfólio de activos, será possível maximizar o seu valor total ao longo do
tempo. Por isso, a concentração da carteira de investimentos no mercado
accionista e de Investimentos Alternativos proporciona ganhos mais altos
mas que trazem maior volatilidade. A Fundação tem também como objectivo
ultrapassar o desempenho do mercado para o que procura os gestores para
cada classe de activos com reconhecidos registos de retornos ponderados
pelo risco associado.
4. Ao longo de 2010 gerou-se um grande debate a propósito do Euro tendo como
pano de fundo o que sucedeu no segundo trimestre com a “crise da Grécia”.
Os mercados accionistas em todo o mundo caíram entre 15 a 25% ao mesmo
tempo que a Grécia ficou debaixo de rigoroso escrutínio o que forçou a União
Europeia a lançar o “Fundo Europeu de Estabilidade Financeira (FEEF)” em Maio
de 2010. Tratou-se dum “pacote de salvamento financeiro” para acudir aos
países-membros da área do euro em caso de dificuldades de financiamento.
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A incerteza provocada no Euro levou-o a uma perda de 6,5% relativamente ao
dólar americano no fim do ano.
5.O que aconteceu em 2009 é que vários Endowments e Fundações alteraram
as suas políticas de alocações de activos para posturas conservadoras em
alturas próximas do ponto mais baixo de cotações. É importante recordar
que, reagir a situações de pânico nos mercados financeiros raramente é uma
boa opção. A Fundação Champalimaud estabeleceu uma prudente política
para resistir a diferentes ciclos de mercado e riscos exogéneos (tal como
os continuados riscos soberanos semelhantes aos da crise grega referida
atrás).
6.Embora a recuperação económica estivesse em terreno firme desde que os
mercados atingiram o seu ponto mais baixo em 2009, tornava-se cada vez
mais evidente um abrandamento que haveria de dificultar uma recuperação
prolongada. Nos EUA, dados desanimadores de emprego e de vendas de
casas, criaram o receio de que a economia recuaria a meio do ano. Em
resposta a esta situação, o FED anunciou no fim de Agosto a intenção duma
segunda ajuda financeira substantiva, designada por “QE2”. Em Setembro
o plano estava finalizado e o FED anunciou a intenção de comprar 600 mil
milhões de obrigações do tesouro americano.
7. Esta iniciativa trouxe as taxas de juro para níveis muito baixos o que ajudou
à recuperação económica e, simultaneamente encorajou os investidores
a procurarem grandes retornos em investimentos de maior risco (acções
e obrigações privadas). Com o abaixamento das taxas de juro e com as
facilidades criadas de acesso a crédito, as acções acabaram o ano com
uma valorização de 11% (MSCI World), as Obrigações de Taxa Fixa, entre 8%
a 15%, as Commodities 17% e os 6%.
8.Em 2011, a tendência muito positiva dos mercados que vinha desde o início do
IV trimestre de 2010, abrandou em Março com os tumultos do Médio Oriente
e Norte de África e, a seguir, com o terramoto do Japão e a situação nuclear
desencadeada. O Médio Oriente e o Norte de África representam 35% da
oferta mundial de petróleo e a actual corrente democrática que varre estas
regiões poderá pôr pressão nalguns dos mais importantes produtores (como
a Arabia Saudita). Os tumultos actuais na Líbia, Iémen, Bahrein e Síria, depois
dos exemplos bem-sucedidos de derrubes de governos como no Egipto e na
Tunísia, parecem não vir a abrandar.
9. No Japão, 3ª economia mundial e uma força dominante na economia global, as
contínuas repercussões do desastre dos reactores nucleares poderão causar
uma séria contracção na economia da região. Mas por agora parece que a
situação está controlada.
125
10. A Fundação tomou medidas substanciais de redução de risco em Fevereiro
e Março com a diminuição de exposição no mercado accionista - venda de
5 a 15% da maioria do portfólio de acções -, evitando-se perdas maiores.
A 14 de Março os activos da Fundação estavam avaliados em 449.120.430€
depois da liquidação de 19 milhões de euros de empréstimos contraídos
para a construção do Centro Champalimaud, com o objectivo da redução da
alavancagem da sua carteira de investimentos.
Lisboa, 8 de Abril de 2011.
A Administração,
126
FUNDAÇÃO D. ANNA DE SOMMER CHAMPALIMAUD E DR. CARLOS
MONTEZ CHAMPALIMAUD
BALANÇO EM 31 DE DEZEMBRO DE 2010 E 2009
(Montantes expressos em euros)
ACTIVO
ACTIVO NÃO CORRENTE:
Activos fixos tangiveis
Propriedades de investimento
Activos intangíveis
Outras contas a receber
Activos biológicos
Participações financeiras
Participações financeiras - outros métodos
Accionistas / sócios
Outros activos financeiros
Activos por impostos diferidos
Outros activos não correntes
Total do activo não corrente
ACTIVO CORRENTE:
Inventários
Activos biológicos
Clientes
Adiantamentos a fornecedores
Estado e outros entes públicos
Outras contas a receber
Diferimentos
Activos financeiros detidos para negociação
Activos financeiros disponíveis para venda
Activos não correntes detidos para venda
Caixa e depósitos bancários
Total do activo corrente
Notas
2010
2009
5
146.296.558
50.206.878
7
33.746
-
34.752
-
8
348.870.798
348.964.957
-
-
495.201.102
399.206.587
639
805.025
457.804
33.573
56.031.467
9.930.721
274.224
45.220
57.754.058
6.009.888
63.338.396
3.931.099
71.935.321
558.539.498
471.141.908
11
389.669.400
389.669.400
11
11
5.010.594
(22.594.003)
4.648.897
(14.018.659)
176.618
372.262.609
(2.545.901)
369.716.708
161.778
380.461.416
(8.575.344)
371.886.072
9
14
9
10
9
9
Total do activo
CAPITAL PRÓPRIO E PASSIVO
CAPITAL PRÓPRIO:
Capital realizado
Acções (quotas) próprias
Outros instrumentos de capital próprio
Prémios de emissão
Reservas legais
Outras reservas
Resultados transitados
Ajustamentos em activos financeiros
Excedentes de revalorização
Outras variações no capital próprio
11
Resultado líquido do período
Total do capital próprio
PASSIVO:
PASSIVO NÃO CORRENTE:
Provisões
Financiamentos obtidos
Responsabilidades por benefícios pós-emprego
Passivos por impostos diferidos
Outras contas a pagar
Total do passivo não corrente
PASSIVO CORRENTE:
Fornecedores
Adiantamentos de clientes
Estado e outros entes publicos
Financiamentos obtidos
Outras contas a pagar
Diferimentos
Passivos financeiros detidos para negociação
Outros passivos financeiros
Passivos não correntes detidos para venda
Total do passivo corrente
-
-
12
43.120.543
43.120.543
43.120.543
43.120.543
13
43.383
30.940
15
13
13
14
3.437.048
118.462.959
22.917.625
672.715
2.722.159
50.400.105
2.000.073
916.716
13
168.517
65.300
145.702.247
188.822.790
56.135.293
99.255.836
558.539.498
471.141.908
Total do passivo
Total do capital próprio e do passivo
O anexo faz parte integrante do balanço em 31 de Dezembro de 2010
Técnico Oficial de Contas
O Conselho de Administração
FUNDAÇÃO D. ANNA DE SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ
CHAMPALIMAUD
DEMONSTRAÇÃO DOS RESULTADOS POR NATUREZAS
DO EXERCÍCIO FINDO EM 31 DE DEZEMBRO DE 2010 E 2009
(Montantes expressos em euros)
RENDIMENTOS E GASTOS
Vendas e serviços prestados
Subsídios à exploração
Ganhos / perdas imputados de subsidiárias, associadas e empreendimentos conjuntos
Variação nos inventários da produção
Trabalhos para a própria entidade
Custo das mercadorias vendidas e das matérias consumidas
Fornecimentos e serviços externos
Gastos com o pessoal
Imparidade de inventários (perdas / reversões)
Imparidade de dívidas a receber (perdas / reversões)
Provisões (aumentos / reduções)
Imparidade de investimentos não depreciáveis / amortizáveis (perdas / reversões)
Aumentos / reduções de justo valor
Outros rendimentos e ganhos
Outros gastos e perdas
Notas
Resultado operacional (antes de gastos de financiamento e impostos)
Juros e rendimentos similares obtidos
Juros e gastos similares suportados
2009
22
(44.161)
(50.114)
17
18
(2.464.135)
(147.833)
(1.713.573)
(5.349)
9
20
21
(103.217)
7.566.852
(7.139.931)
965.132
2.149.905
(9.712.686)
(2.332.427)
(8.366.686)
(213.474)
(208.659)
(2.545.901)
(8.575.344)
Resultado antes de depreciações, gastos de financiamento e impostos
Gastos / reversões de depreciação e de amortização
Imparidade de investimentos depreciáveis / amortizáveis (perdas / reversões)
2010
19
-
-
Resultado antes de impostos
(2.545.901)
(8.575.344)
Resultado líquido do período
(2.545.901)
(8.575.344)
Imposto sobre o rendimento do período
Resultado das actividades descontinuadas (líquido de impostos) incluído no resultado líquido do
período
Resultado por acção básico
O anexo faz parte integrante da demonstração dos resultados por naturezas do exercício findo em 31 de Dezembro de 2010
Técnico Oficial de Contas
O Conselho de Administração

Relatório Anual 2010

Transcrição

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