Added value and positioning of the project

Added value

The clinical research program of the FHU will rely on the 3 specialized obesity centers (CSO). These CSOs coordinate the management of obese patients medically and surgically. One of the objectives of the FHU will be to recruit patients at each site to build a multi-site cohort. For this purpose, we will follow the frame used for ALDEPI / OBESEPI mono-site cohort of patients with morbid obesity and Bariatric surgery form CHRU of Nancy. Sharing the expertise of the three sites, beyond the constitution of this cohort, we will optimize the management of patients by allowing them to benefit from the advances that will be produced in terms of biomarkers, evaluation of existing treatments and screening and management of complications related to bariatric surgery, including micronutrient deficiencies. We will pursue the same objective with the SuRV cohort, which will recruit a cohort of patients with NASH or metabolic cirrhosis at the three sites, with follow-up every six months.

The experimental studies carried out on our original models will benefit from the complementary expertise of partners. Thus, each of the animal models of metabolic syndrome, including the Mucdhl mouse model, the fetal programming MDD rat model and the transgenic mouse models will be evaluated according to the aims shared by all partners in Work Package 1 in relation to homeostasis of the digestive barrier, cell stress and autophagy, genomic / epigenomic / metabolic interactions and remodelling of extracellular matrix. They will benefit from our shared technical expertise, for example animal metabolic imaging, in situ metabolomics of tissue, epigenomics, integrative bio-info, etc. In Work Package 3, the evaluation of repurposed drugs and biomolecules by the different partners will benefit from the experience of Labex Medalis, which has cutting-edge technical resources and project-carrying expertise to develop preclinical and proof-of concept (POC) studies derived from experimental results with high therapeutic potential.

Positioning

The consortium includes world leading experts and teams in their respective fields who are eminently suited to their roles in the project. For example, JL Guéant is a world leading expert in 1-CM, folate and B12 and epigenomic/genomics/nutrition crosstalk in mechanisms of pathological obesity and inherited metabolic diseases, S Muller, co-founder of two SMEs, Neosystem and ImmuPharma, CNRS Silver Medal Award and Innovation Award, a world leading expert in drug discovery and development related to autophagy, JP Bronowicki a world leading expert and coordinator of major international clinical trials in liver diseases, including NASH, R Ricci, recipient of EMBO young Investigator Award and ERC consolidator grant, a world leading expert on signalling pathways of metabolic diseases, C Tomasetto, a world leading expert who co-discovered Ghrelin, a master molecule of nutritional homeostasis, D Meyre, a worl leading expert of genetics of obesity, JN Freund is a world leading expert in homeotic genes of the digestive tract, P Gillery in the field of carbamylation and glycation of proteins in chronic diseases, E Andres in telemedicine and nutritional management of chronic diseases and F Guillemin in measurement of perceived health and measurement and intervention research in chronic diseases and population health. This is illustrated by recent top ranked publications of these team leaders on FHU topic in journals such as Science, Nature communication, Cell Metab, J Exp Med, Lancet Diabetes Endocrinol, Gut, J Hepatol, PNAS, Nucleic Acid Research, Am J Hum Genet, EMBO Rep., Nature Medicine, Nature Rev. Drug Discovery. For example, we were the first to discover the mechanisms of foetal programming of metabolic syndrome linked to MDD during gestation (Blaise et al, Am J Physiol Endocrinol Metab 2007). The Mucdhl model opens very original perspectives on the links between metabolic syndrome and homeostasis of epithelial barriers. The studies of cellular stress, MAPK p38delta and autophagy, extracellular matrix open very original therapeutic perspectives. These different pathomechanisms have a strong potential to fit in an integrated and systemic view that contribute to better explain the metabolic syndrome and other pathological manifestations of obesity.

The originality and synergies of the FHU project is unique in the national and international landscape:

1- In contrast to other centers, we will study the trajectory of pathological obesity along life, relying on French and international “sister” cohorts of obese patients at different ages and conditions, pregnancy, newborns, children, middle-aged subjects and elderly subjects.

2- To our knowledge, this trajectory is a unique initiative in the French and European landscape, which brings together expertise to dissect the interactions between cellular stress, reshaping of the extracellular matrix, innate immunity, epigenome, genome, dysbiosis/metabolism/nutrition crosstalk in the understanding of the complex mechanisms of these diseases. This integrated approach is necessary to design new personalized medicine and therapy tools.

3- Compared to the large number of studies on overeating in the generation of metabolic syndrome and NASH, little attention has been paid to micronutrient deficits. 5 to 15% of the general population and 30 to 50% of patients with bariatric surgery have a deficit in methyl donors, which can influence epigenomic mechanisms. We will assess these mechanisms and translate the knowledge therapeutically.

4- The trajectory will have the major challenge of transforming the “big data” of our cohorts and our clinical trials into the knowledge necessary to design innovative strategies in personalized medicine. Big data analysis has the capacity to provide the « tools » necessary to face the challenges generated by personalized medicine. We will identify the most relevant biomarkers and validate them by replication in sister cohorts. We (David Meyre) participate in major international consortia on pathological obesity.

5- The development of innovative therapies is a central component of the FHU. We rely on the capacities by the SMEs Innotrem and PAT, the resources of the OMAGE regional project / network on high throughput screening methodologies, preclinical models and expertise in clinical trials and our unique libraries of small molecules and evaluation of repurposed molecules.