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Directory Institute Pathophysiology Circulatory system, Hemostasis, Metabolism & Pneumology, Dermatology, Nutrition Diabetes, Metabolism/Nutrition, Endocrinology Gastroenterology, Hepatology, Uro-Nephrology, Osteoarticular system - July 2018 - 1 Table of contents Introduction p 3 Research Teams Circulatory system p 12 Hemostasis p 74 Pneumology p 79 Dermatology p 100 Diabetes p 105 Metabolism/Nutrition p 123 Endocrinology p 197 Gastro-enterology p 216 Hepatology p 229 Uro-Nephrology p 237 Osteo-articular system p 250 2 Introduction 3 1 – Fields covered The life science Institute Pathophysiology, Metabolism & Nutrition (PMN) covers a wide spectrum of research in physiology, experimental medicine and human diseases. The fields covered include heart and vessels, lungs, endocrine organs, liver, kidney, skin, joints and bones, and organs involved in nutrient processing, from all aspects of nutrition, from the control of food intake and nutritional behavior to digestive processing, control of substrate use and storage. The diseases in question frequently show common biological mechanisms and often lack of suitable treatments designed on a pathophysiological basis. 2 – Major scientific challenges in biology and medicine Public health care challenges Among diseases within the PMN scope, cardiovascular, respiratory, metabolic and nutritional diseases with their devastating complications represent a major public health care challenge. Diabetes, hyperlipidemia, obesity, renal insufficiency lead to cardiovascular disease, the major cause of mortality in industrialized countries and usually develop in relation with atherosclerosis. Coronary artery disease, stroke and chronic heart failure are responsible for 75% of cardiovascular-related deaths. They represent 29% of deaths in France, almost equaling deaths due to cancer. Thrombotic diseases are very prevalent, arterial thrombosis (ischaemic diseases) and venous thrombosis (thrombo-embolic disease) are the world's leading cause of death. The prevalence of constitutional haemorrhagic diseases is limited, but their social and economic impact is significant, as in the case of haemophilia. Respiratory diseases (asthma, chronic obstructive pulmonary disease, COPD; pulmonary fibroses) affect millions of people in France and their incidence is increasing. COPD alone already represents the third-largest cause of death in Europe (sixth in the world). The prevalence of diabetes is 7.4% in France in the age range 20 to 79 (IDF 2015). The increasing prevalence of diabetes parallels that of obesity, which raised to 15.8% among men and 15.6% among women in France (age range 30 to 69, INVS 2013). Regarding the visceral obesity the prevalence reaches 41.6% and 48.5% respectively. Diabetes is among the leading causes of blindness, end stage renal disease, non-traumatic limb amputation in adults and coronary heart disease. Type 2 diabetes is a multifactorial disease that shows heterogeneity in many respects and is often a manifestation of a much broader underlying disorder often referred to as the metabolic syndrome, an operational paradigm that includes hyperinsulinaemia, dyslipidaemia, hypertension, visceral obesity, hypercoagulability and microalbuminuria. Metabolic syndrome also leads to various non-vascular complications, including steatohepatis, cirrhosis or arthrosis. The metabolic epidemics and its cardiovascular complications although world-wide have been most pronounced in non- European populations, as shown by studies from Native American and Canadian communities, Pacific and Indian Ocean island populations or populations throughout Asia. Paradoxically, malnutrition is also a major threat to global human health and survival. Recent estimates indicate that nutritional deficiencies account for 3 million child deaths each year in less- developed countries while progress toward designing effective life-saving interventions is currently hampered by serious gaps in our understanding of nutrient metabolism in the human. Denutrition is further observed in 40% of patients suffering from chronic diseases, in 30 to 50% of hospitalized patients of all pathologies and is an independent factor for morbidity/mortality. Overall, there is a need for an increased research effort focusing on nutrition and its disorders, including the interrelationship with the environment, the human microbiome, digestive physiology, nutritional behaviors or food security. Diseases of the bones and joints are also a concern for the French, particularly due to ageing of the population. On their own they represent half of chronic diseases in people over 65 and are a major cause of invalidity (arthrosis is the second largest handicap factor in men, the fourth in women). 4 Among the over 50s, one women in four and one man in eight will be affected by osteoporosis during their lives. Skin diseases include a proportion of allergic complaints (atopic dermatitis, contact eczema, occupational dermatoses, photo-allergies, urticaria and skin accidents due to oral administration of a drug (toxicodermatitis)) and a proportion of chronic inflammatory disorders (psoriasis, atopic dermatitis, pelada, etc.). Among this latter group, psoriasis, affects between two and three million people in France and is associated with a significant change in the quality of life, often leading to a severe social handicap. The impact of this dermatosis on the quality of life is as significant as that caused by asthma, diabetes or chronic cardiac ischaemic diseases. The social cost of psoriasis is therefore considerable. Ageing of the population is increasingly frequently accompanied by chronic vascular complaints of the lower limbs. Their treatment is complex and should be multi-disciplinary, ideally as part of a care network led by dermatologists specialised in the field of cicatrisation. Other diseases that are in the scope of the Institute are frequent and/or carry high morbidity/mortality rates. Basic and clinical research is required to progress in our understanding of the mechanisms involved in cardiac, vascular, respiratory, renal, endocrine, digestive, dermatologic and osteoarticular disorders. Scientific challenges Diseases implicating heart and vessels, lungs, endocrine tissues, kidney, liver, skin, bone and joints and the digestive tract, although organ-specific, cannot be considered independently of the numerous interactions with the whole organism and the environment. Transversal aspects of physiology and pathology will be emphasized within the scope of the PMN Institute. Underlying fundamental research and biological issues that need to be addressed correspondingly cover a large field of disciplines requiring strong links between institutional partners, as well as with industrial partners. All these diseases share: 1- an incomplete knowledge of the genes involved in their etiology, a situation which is rapidly changing thanks in particular to the new genomic approaches, 2- an insufficient basic knowledge of gene and protein functions in target organs as well as their interaction with the environment; 3- incomplete understanding of pathophysiological mechanisms of diseases expressed within corresponding tissues, i.e. of mechanisms of initiation and progression of disease processes; 4- the general insufficiency of available treatments and preventive strategies based on a better understanding of the mechanisms of common diseases; 5- the understudied strategies of cell therapy, which could benefit to many of these diseases; 6- the importance of discovering new biomarkers that would be useful for diagnostic, prognostic and treatment guidance. 1) Gene/protein-function studies in physiology and interactions with environment The availability of gene sequences encoding for molecules of unknown functions emphasizes the need for extensive gene-function studies and for the characterization of tissue distribution of newly identified genes. As part of this task, the development of new models to empower these studies is required. Other emphasis is required on development biology, on studies of ageing mechanisms, on comparative genomics with the goal of better understanding of human gene and protein functions, on integrative physiology to decipher signalling and metabolic pathways and interactions at the whole organism level, on the understanding of gene interactions and gene networks that impact on individual cell and tissue functions, on epigenetics and metagenomics to study gene interactions with the environment. The sequence of an increasing number of individual human genomes also paves the path toward in depth understanding of human gene and post- transcriptional diversity in cell, tissue and organ physiology. With few exceptions, the miRNA target genes and the mechanism of target suppression are currently unknown because reliable experimental methods for comprehensively identifying the miRNA targets have yet to be developed. 5 2) Disease-initiating mechanisms and mechanisms of disease progression in common diseases. Mechanisms that trigger destructive processes within target tissues are seldom identified. Other than certain rare monogenic diseases involving key genes in cell function, common diseases usually develop on a multigenic susceptibility background associating “normal” gene variants, often affecting quantitative traits (intermediate phenotypes) that contribute to the clinical phenotype observed, most often interacting with environmental factors as part of a multifactorial process. As triggering factors remain elusive in most cases, new hypotheses

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