Discovery consists of seeing “ “ what everybody has seen, and thinking what nobody has thought. Albert SZENT-GYORGYI, 1937 Nobel Prize for Medicine 1 ADMINISTRATIVE STRUCTURE The administrative structure of the Institute is composed of an Institute Administrative Coordinator, a Clinical Research Unit and the Logistics and Accounts Unit. This structure ensures a transversal support to all Research Groups. Institutes Administrative Coordinator (CAI): Michel Van Hassel Clinical Research Unit: Regulatory Affairs, Quality, Contract-Budget Analysis of Clinical Trials Clémentine Janssens Valérie Buchet Salvatore Livolsi Marie Masson Dominique Van Ophem Logistics and Accounts Unit: Maimouna Elmjouzi MBLG/CTMA Myriam Goosse-Roblain MIRO Eric Legrand CHEX Cyril Mougin FATH/RUMA Michel Notteghem CARD/EDIN Dora Ourives Sereno GYNE/PEDI/GAEN Nadtha Panin LTAP IREC General Address: Avenue Hippocrate, 55 bte B1.55.02 1200 Woluwe-Saint-Lambert Internet Address: http://www.uclouvain.be/irec.html 2 The Institute brings together different research groups who work to improve our understanding of disease mechanisms, as well as to discover and/or develop new therapeutic strategies. Basic research joins clinical research in an enriching environment where clinical scientists and basic researchers can exchange their experiences and work on common projects. Our focus is thus clearly on translational research. Research at our Institute covers a wide range of biomedical problems and is mostly organized in an organ or system specific manner. The Institute is composed of 21 research groups working in close collaboration with the Cliniques universitaires Saint- Luc, in Brussels, and Mont-Godinne, in Yvoir. The Institute brings together more than 500 researchers and PhD students of different horizons and provides logistical support for both basic and clinical research. Jean-Luc Balligand IREC President 3 RESEARCH EXPENDITURES AT INSTITUTIONAL LEVEL 2010-2014(K€): 4 NEW RESEARCH AGREEMENTS AND CONTRACTS CONCLUDED 2011-2015: 5 RESEARCH GROUPS Cardiovascular Research (CARD) 07 Computer Assisted Robotic Surgery (CARS) 24 Experimental Surgery and Transplantation (CHEX) 36 Endocrinology, Diabetes and Nutrition (EDIN) 46 Epidemiology and biostatistics (EPID) 56 Pharmacology and Therapeutics (FATH) 62 Hepato-Gastro-Enterology (GAEN) 77 Gynecology (GYNE) 88 Medical Imaging Research (IMAG) 100 Louvain Centre for Toxicology and Applied Pharmacology (LTAP) 124 Medical Microbiology (MBLG) 134 Molecular Imaging, Radiotherapy and Oncology (MIRO) 146 Morphology (MORF) 160 Nephrology (NEFR) 174 Pediatrics (PEDI) 178 Pneumology, ENT and Dermatology (PNEU) 190 Rheumatic Pathology (RUMA) 196 Centre for Applied Molecular Technologies (CTMA) 202 6 EXPERIMENTAL RESEARCH GROUP CLINICAL RESEARCH GROUP R Magali BALTEAU, Postdoctoral Fellow R Valerie LACROIX, PhD Student R Diego CASTANARES, Postdoctoral Fellow R Florence MAILLEUX, PhD Student R Evangelos P DASKALOPOULOS, Postdoctoral Fellow R Frederick MAES, PhD Student R Yeliz ANGIN, Postdoctoral Fellow R Julie MELCHIOR, PhD student R Gauthier-Thibaut NOPPE, PhD Student R R Jean-Louis Christophe BEAULOYE Mihaela AMZULESCU, PhD student Matteo PETTINARI, PhD Student VANOVERSCHELDE MD, PhD R Julien AUQUIER, PhD student R Sophie PIERARD, PhD Student MD, PhD R Jamila BOULIF, PhD student R Edith RENGUET, PhD Student R Christophe de MEESTER, PhD student R Nawal REZZOUG, PhD Student R Fabian DEMEURE, PhD Student R Clothilde ROY, PhD Student R Cécile DUFEYS, PhD Student R Allison SLIMAIN, PhD Student R Shakeel KAUTBALLY, PhD student R Stéphanie SELDRIUM , PhD Student R Sophie LEPROPRE, PhD Student R Aurélie TIMMERMANS, PhD Student R Olivier VAN CAENEGEM, PhD Student Luc BERTRAND Sandrine HORMAN PhD PhD R Anne VANSTEENBERGEN, PhD Student R Patricia BUCHLIN, Research Scientist R Audrey GINION, Research Scientist R Xavier HAVAUX, Research Scientist R Nicolas MARQUET, Technician R Delphine THIBOU, Animal Technician Bernhard GERBER Agnès PASQUET A-Catherine POULEUR David VANCRAEYNEST MD, PhD MD, PhD MD, PhD MD, PhD Alexandre PERSU Gébrine EL KHOURY Parla ASTARCI Philippe NOIRHOMME Laurent DE Kerchove Joëlle KEFER Jean-Benoît LE POLAIN de WarouX MD, PhD MD, PhD MD, PhD MD, PhD MD, PhD MD, PhD MD, PhD CARDIOVASCULAR RESEARCH (CARD) The importance of cardiovascular disease in terms of public health is well established. Cardiovascular diseases, mainly secondary to atherosclerosis, are responsible for about 50% of deaths in industrialized countries. Since it is not possible to study all aspects of the cardiovascular disease, our research unit has determined its main lines of investigation based on its expertise and know-how and also on the clinical applicability of the scientific topics, which are addressed. Our research focus on 4 main axes : 1. Research on the role of intracellular signalling in cardiovascular diseases like type 2 diabetes, cardiac hypertrophy and heart failure. 2.Research on valvular diseases. 3.Research in cardiac imaging. 4.Research on platelet signaling and metabolism. These 4 main research areas are highly interconnected, integrating both clinical and basic research. Our unit has developed a number of skills ranging from molecular and cell biology to biochemistry and population studies. Our researchers bring their own expertise to the entire research program. 7 EXPERIMENTAL RESEARCH GROUP Role of fibroblastic AMPKα1 in We next examined mechanisms responsible for left ventricular remodeling after the increased LV remodeling in Per-KO mice, fo- cusing on Connexin 43 (Cx43) and lysyl oxidase myocardial infarction (Lox), two proteins critically involved in many aspects of cardiovascular physiology. We found Cécile Dufeys, Evangelos P Daskalopoulos, that Cx43 and Lysyl oxidase (Lox) expression Nicolas Marquet, Christophe Beauloye, were drastically reduced in CF isolated from in- Sandrine Horman farcted Per-KO hearts. This result was confirmed in vitro, in human CF transfected with a specific The term “ventricular remodelling” refers to siRNA targeting AMPKα1. Interestingly, the pro- changes in left ventricle (LV) structure in res- tein levels were decreased at a higher extent than CARDIOVASCULAR RESEARCH CARDIOVASCULAR ponse to physiological and pathological haemo- the mRNA levels, indicating that post-transcrip- dynamic stress. Data of our group strongly sup- tional mechanisms were probably involved in the port that AMP-activated protein kinase (AMPK) AMPKα1-dependent Cx43 and Lox regulation. controls key mechanisms involved in adverse LV remodelling, such as cardiomyocytes hyper- In conclusion, we report that the deletion of trophy and fibrosis. However, a crucial question AMPKα1, specifically in CF, promotes LV dilata- remains unsolved. It is not known which cardiac tion after MI. We identified Cx43 and Lox as two cell types play the predominant role in the pro- new downstream targets of AMPKα1, and likely tective effect of AMPK. This is due to the fact mediators of its function in the control of CF bio- that most of the studies performed on animal logy and LV remodeling (Figure 1). The obtained models used for genetic invalidation of AMPK data support the emergent notion that therapeu- are whole-body knockout (KO) of AMPK catalytic tic modulation of CF function may represent a subunits. The generation of tissue-specific and novel approach to the prevention and/or treat- conditional KO animals where AMPK is selecti- ment of heart failure. ¢ vely invalidated in specific cardiac cell types will allow to better determine the relative impact of each AMPK action on cardiac pathology. The hypothesis that drives this project, and which is strongly supported by our previous and current studies, is that AMPKα1 from cardiac fibroblasts (CF) is a central player in the func- tional and structural adaptation of the heart in response to cardiac injury. We therefore generated a mouse strain (Perios- tin-Cre+/AMPKα1fl/fl) in which AMPKα1 can be specifically invalidated in CF in response to myo- cardial infarction (MI), induced by the permanent ligation of the left anterior coronary artery (Per- Figure 1 : Role of AMPK in the ischaemic and post-is- KO). We show that infarct size was not different chaemic heart. AMPK prevents the progression of adverse LV remodeling (1) by increasing the survival of cardiomyo- between WT and Per-KO mice. At basal state, cytes during ischemia and the post-ischemic period, (2) WT and Per-KO hearts were comparable, but 4 by contributing to the formation of a mature collagen scar weeks after MI, Per-KO mice had a greater in- through the control of fibroblastic properties via a mecha- crease in end-diastolic and end-systolic dimen- nism involving regulation of Cx43 and Lox. sions in comparison to WT, reflecting an accele- rated dilatative remodeling. 8 Elucidation of the molecular mechanisms involved in the insulin-sensitizing effect of AMPK on cardiac glucose uptake Julien Auquier, Audrey Ginion, Edith Renguet, Christophe Beauloye, Sandrine Horman, Luc Bertrand Diabetic hearts are known to be more suscep- tible to myocardial infarction. Insulin resistance and its consequence, the impairment of glucose Figure 2 : Molecular signalling involved in the regulation of cardiac glucose uptake by insulin and AMPK. Insulin uptake, are partially responsible for this vulne- binds to its receptor (IR) and activates PKB via the insulin rability. In previous work, we discovered that receptor substrate 1 (IRS-1)/phosphatidylinositol-3 kinase RESEARCH CARDIOVASCULAR pharmacological activation of AMPK, including (PI3K) pathway.