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LUPUS AND AUTOREACTIVE IMMUNE REPERTOIRES Constantin Fesel Research Fellow PhD in Immunology, Université Paris VI, 1998 Post-doctoral Fellow, Weizmann Institute of Science, Rehovot Principal Investigator at the IGC since 2001 While the detection of molecular mechanisms as well as of genetic disease risk factors rapidly evolves, the systemic diversification of specificity repertoires is still badly understood. In this situation, it is increasingly relevant to model the pathogenetic process that leads to autoimmune diseases as a whole, since they are known to depend on complex interactions of molecular and cellular mechanisms. Systemic Lupus Erythematosis (SLE) is a human autoimmune disorder where altered physiologies and self-reactive repertoires of both B- and T-cells are intimately connected. Our approach is to model, in a stepwise fashion, the ways in which genetic factors and molecular mechanisms are interconnected. Since we found particular relations between antibody reactivity and regulatory T-cells in unaffected relatives of SLE patients who often share SLE-associated autoantibodies, our hypothesis is that these autoantibody-positive relatives bear a particular capacity to regulate autoimmune reactions. GROUP MEMBERS Nuno Costa (Research Technician) Sandra Iris Godinho (Masters student) COLLABORATORS Maria Berta Silva Martins (Instituto de Ciências Biomédicas Abel Salazar, Porto, Portugal) Carlos Vasconcelos (Hospital Geral de Santo Antonio, Porto, Portugal) Margarida Lima (Hospital Geral de Santo Antonio, Porto, Portugal) Cristina João (Centro de Investigação de Patologia Molecular, Lisboa, Portugal) Carlos Ferreira (Hospital de Santa Maria, Lisboa, Portugal) Maria Francisca Fontes (Hospital Curry Cabral, Lisboa, Portugal) José Alves (Hospital Fernando Fonseca, Amadora-Sintra, Portugal) FUNDING Fundação para a Ciência e Tecnologia (FCT), Portugal LUPUS AND ITS COMPENSATION IN UNAFFECTED RELATIVES BY T-CELL REGULATION SLE is an autoimmune disease characterised by autoantibodies that accumulate over years before clinical manifestation. Unaffected relatives of SLE patients frequently share SLE-type autoantibodies, most without ever acquiring clinical disease, which suggests a capacity to compensate pathogenic effects associated with them. A therapy that is able to restore such compensation appears highly desirable. Conversely to reported negative correlations of regulatory T- cells with circulating IgG autoantibodies in patients, we found them positively correlated in unaffected relatives. Furthermore, autoantibody profiles were influenced by genetic polymorphisms affecting effects mediated by IL2, the cytokine with the strongest impact on Treg function in characteristic ways. We hypothesise that an IL2-dependent regulatory feedback mechanism, abrogated in manifest SLE, can control the pathogenicity of SLE-type antibody production. We are now characterising this mechanism. Data analysis is in progress Scheme of SLE pathogenesis according to current knowledge, with the role of regulatory T-cells indicated. Cytogramme with subsets of conventional and regulatory T-cells. IGC ANNUAL REPORT ‘11 RESEARCH FELLOWS 74
NEURONAL STRUCTURE AND FUNCTION Inbal Israely Research Fellow PhD in Neuroscience, University of California, Los Angeles, 2004 Post-doctoral Associate, MIT, USA THIS GROUP IS A MEMBER OF THE CHAMPALIMAUD NEUROSCIENCE PROGRAMME AT THE IGC Research Fellow at the IGC since 2009 link to external website We are interested in understanding how activity can lead to specific structural changes in neurons which may be important for learning, and how such changes affect connectivity within neural circuits. It is unknown how the diverse forms of activity that a neuron receives are physically stored and regulated at the level of individual spines, the sites of neuronal connections. Does long lasting depression lead to structural changes at synapses? What types of structural and electrophysiological modifications take place at spines following complex patterns of naturally occurring activity? Several mental retardation disorders in humans are characterised by abnormal spine morphology, and studying neurons from animal models may further our understanding of the relationship between structure and function. We aim to combine molecular and genetic tools with imaging and electrophysiological methodologies, to determine how information is physically stored in the brain. GROUP MEMBERS Yazmin Ramiro Cortes (Post-doc) Anna Hobbiss (PhD Student) Ali Ozgur Argunsah (PhD Student) COLLABORATORS Thomas McHugh (Riken Brain Science Institute, Japan) Devrim Ünay (Bahcesehir University, Turkey) FUNDING Champalimaud Foundation (CF), Portugal Bial Foundation, Portugal DENDRITIC COMPARTMENTALISATION OF PROTEIN SYNTHESIS-DEPENDENT SYNAPTIC PLASTICITY We found that protein synthesis dependent stimulation of spines can facilitate plasticity at neighbouring spines for up to an hour and over long distances (70 micra). Through 2-photon imaging and uncaging of glutamate at individual spines, we aim to visualise structural changes that occur 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 aim to determine whether competition for proteins during synaptic plasticity can shape the organization of inputs within a dendrite, leading to the physical clustering of synapses. We also investigate whether the clustering of synapses can be observed following the development of neural circuits, by examining the endogenous distribution of spines within dendrites of the hippocampus. We find that the stimulation of multiple spines closely together in time can lead to competition for cellular resources, and that new proteins are required for this process. These findings demonstrate that synaptic plasticity may be biologically constrained, and provides a potential mechanism through which synapses could be spatially clustered. We are examining the parameters over which competition is regulated, in order to define the learning rules for protein synthesis dependent plasticity. STRUCTURAL CORRELATES OF SYNAPTIC DEPRESSION AT DENDRITIC SPINES Synaptic potentiation leads to an enlargement of spine head volumes at individual synapses, however the structural correlates of synaptic depression are poorly understood. Long term depression can be initiated through a variety of receptors, and it is unknown whether the structural correlates of this form of plasticity apply generally to any decrease of synaptic weight, or whether there are specific modifications depending on which signalling pathway is activated. We aim to determine what are the structural correlates of synaptic depression at dendritic spines. In particular, we are interested in exploring long lasting forms of synaptic depression that depend on new protein synthesis. We will determine what are the parameters which govern these changes following activity at specific inputs. Additionally, we will probe whether new proteins serve to constrain plasticity at multiple spines similarly to the case for long term potentiation. We have induced long lasting synaptic depression through the activation of metabotropic glutamate receptors (mGluRs) in hippocampal organotypic slice cultures. We have quantified the structural changes which correlate with this form of plasticity through 2-photon imaging of subsets of spines for up to four hours. Additionally, we recorded electrophysiological responses from these cells in order to monitor the changes following synaptic plasticity. INDUCING ACTIVITY AT SINGLE DENDRITIC SPINES TO STUDY STRUCTURAL DYNAMICS. Using 2-photon microscopy in living brain slices together with photoactivation of caged glutamate, we can examine how neurons physically store information at synapses. We can vary the type of stimulation delivered at a given input to mimic different forms of activity, and study what are the structural and functional correlates. We also examine how a neuron integrates information arriving at multiple synapses. IGC ANNUAL REPORT ‘11 RESEARCH FELLOWS 75
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The Instituto Gulbenkian de Ciênci
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ORGANISATION CALOUSTE GULBENKIAN FO
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established a unique and diverse hu
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After all these years of a half-dis
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IGC ANNUAL REPORT ‘11 THE DIRECTO
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30 Nationalities working at the IGC
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2004 - 2011 NEW RESEARCH GRANTS BRE
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PROTEIN-NUCLEIC ACIDS INTERACTIONS
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MEIOSIS AND DEVELOPMENT Vítor Barb
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EPIGENETICS AND SOMA Vasco M. Barre
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Page 25 and 26: as a manuscript submitted in 2011 (
Page 27 and 28: We have found a new precursor struc
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Page 31 and 32: POPULATION AND CONSERVATION GENETIC
Page 33 and 34: NEUROBIOLOGY OF ACTION Rui M. Costa
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Page 37 and 38: CELL BIOPHYSICS AND DEVELOPMENT Jos
Page 39 and 40: GENOME-WIDE ANALYSIS OF TELOMERE PR
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Page 43 and 44: ACTIN DYNAMICS Florence Janody Prin
Page 45 and 46: EPIGENETIC MECHANISMS Lars Jansen P
Page 47 and 48: SYSTEMS NEUROSCIENCE THIS GROUP IS
Page 49 and 50: PATTERNING AND MORPHOGENESIS Moisé
Page 51 and 52: EARLY FLY DEVELOPMENT Rui Gonçalo
Page 53 and 54: BEHAVIOURAL NEUROSCIENCE THIS GROUP
Page 55 and 56: DISEASE GENETICS Carlos Penha Gonç
Page 57 and 58: COMPUTATIONAL GENOMICS José Pereir
Page 59 and 60: COMPLEX ADAPTIVE SYSTEMS AND COMPUT
Page 61 and 62: hypothesis that expression of HO-1
Page 63 and 64: hemocyte purification using a combi
Page 65 and 66: EVOLUTIONARY GENETICS Henrique Teot
Page 67 and 68: BACTERIAL SIGNALLING Karina B. Xavi
Page 69 and 70: BIOPHYSICS AND GENETICS OF MORPHOGE
Page 71 and 72: PLANT GENOMICS Jörg Becker Researc
Page 73: NETWORK MODELLING Claudine Chaouiya
Page 77 and 78: NEUROETHOLOGY LABORATORY THIS GROUP
Page 79 and 80: LEARNING LABORATORY THIS GROUP IS A
Page 81 and 82: IMMUNE REGULATION Carlos E. Tadokor
Page 83 and 84: STRESS AND CYTOSKELETON Escola Supe
Page 85 and 86: ANIMAL FACILITIES Jocelyne Demengeo
Page 87 and 88: TRANSGENICS UNIT Moisés Mallo Head
Page 89 and 90: CELL IMAGING UNIT José Feijó Head
Page 91 and 92: GENOMICS UNIT Carlos Penha Gonçalv
Page 93 and 94: • Low noise (6 Rat arrays for Ins
Page 95 and 96: ION DYNAMICS FACILITY Ana Catarina
Page 97 and 98: BIOINFORMATICS AND COMPUTATIONAL BI
Page 99 and 100: PORTUGUESE BIOINFORMATICS CENTRE Pe
Page 101 and 102: INNOVATION AND TECHNOLOGY TRANSFER
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Page 107 and 108: PUBLICATIONS IGC ANNUAL REPORT ‘1
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Page 119 and 120: IGC ANNUAL REPORT ‘11 PUBLICATION
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Cells to organisms I 24 - 28 Octobe
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INDP - INTERNATIONAL NEUROSCIENCE D
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Extroduction 30 May - 3 June Organi
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PROGRAMME FOR ADVANCED MEDICAL RESE
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GTPB - THE GULBENKIAN TRAINING PROG
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THESES MSc THESES Sofia Pereira Dev
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SEMINARS AT THE IGC JANUARY 2011 DA
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MARCH 2011 DATE SPEAKER AFFILIATION
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MAY 2011 DATE SPEAKER AFFILIATION T
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JULY 2011 DATE SPEAKER AFFILIATION
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OCTOBER 2011 DATE SPEAKER AFFILIATI
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DECEMBER 2011 DATE SPEAKER AFFILIAT
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On the origin and diversification o
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HELENA COSTA Mechanism of IL-8 indu
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Of models and mechanisms of ion dyn
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The centromere: A showcase for epig
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Mechanisms determining adult body s
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The evolutionary dynamics of (Rab)
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HENRIQUE TEÓTONIO The genetic basi
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EMBnet - ANNUAL GENERAL MEETING 201
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PUBLIC ENGAGEMENT IN SCIENCE
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Science Projects Support Programme
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FUNDRAISING Maria João Leão Head
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PARTNERS AND SPONSORS Several partn
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