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INFLAMMATION Miguel P. Soares Principal Investigator PhD in Science, University of Louvain, Belgium, 1995 Research Fellow, Harvard Medical School, Boston, MA, USA Instructor in Surgery, Harvard Medical School, Boston, MA, USA Lecturer, Harvard Medical School, Boston, MA, and USA Invited Professor at Lisbon Medical School, Universidade de Lisboa, Portugal Head of IGC Histopathology Unit Principal Investigator at the IGC since 2004 Inflammation is an immediate response to foreign challenge and/or tissue injury characterised by local and transient extravasation of soluble molecules and leukocytes from blood into non-lymphoid tissues. While the physiologic purpose of inflammation is to restore homeostasis there are many instances where inflammation becomes pathological. Moreover, there is a general consensus that some of the major causes of human morbidity and mortality are in fact due to pathological conditions in which inflammation and/or immunity are the underlying cause of disease. The research effort developed in our laboratory is aimed at understanding the cellular and molecular mechanisms assuring that in the overwhelming majority of cases inflammation exerts its physiologic purpose without becoming pathological. Our body of work supports the notion that one of such mechanisms relies on the expression of cytoprotective genes that allow inflammation to progress without causing irreversible tissue damage. MODULATION OF PROGRAMMED CELL DEATH BY FREE HEME Under homeostasis, the reactivity of heme prosthetic groups is controlled by their insertion into the “heme pockets” of hemoproteins. Under oxidative stress however, some hemoproteins can release their heme prosthetic groups. The non-protein-bound (free) heme becomes highly cytotoxic, most probably due to the Fe atom contained within its protoporphyrin IX ring. When this occurs, free heme can catalyse, in an unfettered manner, the production of free radicals via Fenton chemistry and sensitise cells to undergo programmed cell death. In our laboratory we have shown that the cytotoxic effect of free heme plays an important role in the pathogenesis of a variety of inflammatory diseases in which hemoproteins release their prosthetic heme groups. MECHANISMS OF DISEASE TOLERANCE Malaria, the disease caused by Plasmodium infection, remains one of the main causes of morbidity/mortality worldwide. Epidemiologically however, less than 1-2% of Plasmodium-infected individuals succumb to severe forms of malaria. This suggests that Plasmodium has co-evolved with its human host to reach an evolutionary “trade off” in which infection “rarely” compromises host viability. This trade off is thought to rely almost exclusively on the ability of the host’s immune system to control parasite burden, a defence strategy referred to as resistance to infection. However, there is an additional host defence strategy that operates during Plasmodium infection and that limits disease severity irrespectively of parasite burden, i.e. tolerance to infection. The mechanisms underlying host tolerance to Plasmodium infection remain poorly understood. We are exploring the hypothesis that several genes that regulate the deleterious effects of free heme might control host tolerance to infection. GROUP MEMBERS Ana Ferreira (Post-doc, left in March) Josina Filipe (Post-doc, left in January) Virgínia Oliveira Marques (Post-doc, left in January) Ana Cunha (Post-doc) Rafaella Gozzelino (Post-doc) Susana Ramos (Post-doc, started in February) Rasmus Larsen (Post-doc) Zélia Gouveia (External PhD Student) Andreia Cunha (PhD student) Nadja Pejanovic (PhD student) Ivo Marguti (PhD student, left in July) Bahtiyar Yilmaz (PhD Student) Sofia Rebelo (Lab Manager) Sílvia Cardoso (Laboratory Assistant) COLLABORATORS Josef Anrather (Cornell University, New York, USA) Leo Otterbein (Harvard Medical School, Boston, USA) Ann Smith (University of Missouri - Kansas City, USA) Ingo Bechmann (Johann Wolfgang Goethe-University, Frankfurt/Main, Germany) Yves Beuzard (Hospital Saint Louis, Paris, France) Lukas Kühn (Ecole Polytechnique Fédérale de Lausanne (EPFL), Switzerland) Carlos Penha Gonçalves (IGC, Portugal) Jocelyne Demengeot (IGC, Portugal) Henrique Silveira (Instituto de Higiene e Medicina Tropical (IHMT), Portugal) Salome Gomes (IBMC- Universidaded do Porto, Portugal) FUNDING FP6 Framework Programme 6, European Commission GEMI Fund Linde Healthcare The Bill & Melinda Gates Foundation, USA Fundação para a Ciência e a Tecnologia (FCT), Portugal PROTECTION AGAINST MALARIA BY "NATURAL" ANTIBODIES We are testing the hypothesis that antibodies directed against a specific carbohydrate produced by gut pathogens might play a role in immunity against severe forms of malaria. Newborns and young children, who are most susceptible to these severe forms of the disease, have not yet built up antibodies to this carbohydrate. We will assess whether stimulating production of this antibody after birth can offer increased protection. REGULATION OF ADAPTIVE IMMUNITY BY HEME OXYGENASE-1 (HO-1) Over the past few years we extended our original studies to test the hypothesis that HO-1 might regulate T cell mediated autoimmunity leading to the pathogenesis of immune mediated inflammatory diseases such as diabetes, arthritis or multiple sclerosis (MS). We found that this is indeed the case for MS, where disease progression is caused by T cell driven neuroinflammation, leading to central nervous system injury. The mechanism underlying the protective effect of HO-1 against autoimmune neuroinflammation is not clear. We are testing the IGC ANNUAL REPORT ‘11 RESEARCH GROUPS 60
hypothesis that expression of HO-1 by antigen presenting cells, and in particular by dendritic cells, regulates their immunogenicity in a manner that arrests the pathogenesis of autoimmune diseases. ANTI-ATHEROGENIC EFFECT OF HEME OXYGENASE-1: MECHANISM OF ACTION Expression of HO-1 exerts anti-atherogenic effects that are mediated, at least in part, by the production of the gasotransmitter carbon monoxide (CO). The hypothesis tested under this project is that CO can prevent the pathogenesis of atherosclerosis via a mechanism that involves the modulation of monocyte/ macrophage activation as well as the inhibition of smooth muscle cell (SMC) proliferation. We have shown that the effect of CO is associated with it's ability to suppress the pro-inflammatory phenotype of monocyte/macrophage activation and to block smooth muscle cell (SMC) proliferation via a sequence of events that requires the activation of the p38 mitogen-activated protein kinases (MAPK). We aim to investigate whether inhaled CO can be used therapeutically to suppress the development of lipid-mediated atherosclerosis. IGC ANNUAL REPORT ‘11 RESEARCH GROUPS 61
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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
Page 9 and 10: After all these years of a half-dis
Page 11 and 12: IGC ANNUAL REPORT ‘11 THE DIRECTO
Page 13 and 14: 30 Nationalities working at the IGC
Page 15 and 16: 2004 - 2011 NEW RESEARCH GRANTS BRE
Page 17 and 18: PROTEIN-NUCLEIC ACIDS INTERACTIONS
Page 19 and 20: MEIOSIS AND DEVELOPMENT Vítor Barb
Page 21 and 22: EPIGENETICS AND SOMA Vasco M. Barre
Page 23 and 24: VARIATION: DEVELOPMENT AND SELECTIO
Page 25 and 26: as a manuscript submitted in 2011 (
Page 27 and 28: We have found a new precursor struc
Page 29 and 30: We have previously developed a sper
Page 31 and 32: POPULATION AND CONSERVATION GENETIC
Page 33 and 34: NEUROBIOLOGY OF ACTION Rui M. Costa
Page 35 and 36: During this year we demonstrated th
Page 37 and 38: CELL BIOPHYSICS AND DEVELOPMENT Jos
Page 39 and 40: GENOME-WIDE ANALYSIS OF TELOMERE PR
Page 41 and 42: Improved ICT techniques and methodo
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: COMPLEX ADAPTIVE SYSTEMS AND COMPUT
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 and 74: NETWORK MODELLING Claudine Chaouiya
Page 75 and 76: NEURONAL STRUCTURE AND FUNCTION Inb
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
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Page 103 and 104: ADMINISTRATION AND ACCOUNTS José M
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IGC ANNUAL REPORT ‘11 PUBLICATION
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António Coutinho Professional Meri
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GRADUATE TRAINING AND EDUCATION
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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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