Project description DEENESFRITPL On the trail of an opioid modulation of insulin secretion Obesity and type 2 diabetes are interrelated, increasingly common and a significant threat to public health. Improved therapies are needed yet a lack of understanding of disease pathology has hindered therapy development. Opioids impact glucose metabolism, which can alter the risk of diabetes development. The EU-funded OpiO project will investigate a potential role of the delta opioid receptor in mediating the metabolic response to opioids in humans. Further, if the delta opioid receptor turns out to play a direct role in modulating insulin secretion from the pancreas, the team will have a new therapeutic target to combat both obesity and type 2 diabetes. Show the project objective Hide the project objective Objective Type 2 diabetes (T2D) and obesity are leading causes of morbidity and mortality, becoming a major burden on public health. Failure to understand their pathophysiology has frustrated efforts to develop improved therapeutic strategies. T2D and obesity are complex polygenic disorders. Genome-wide association studies have identified hundreds of loci associated with metabolic traits, but they have not led to promising new drug targets, so far. In contrast, the identification and characterization of rare mutations causing monogenic metabolic disorders have been instrumental in repositioning or developing drugs. Beyond this proof of concept, the challenge is to use genomic medicine for innovative molecules restoring impaired insulin secretion that characterizes T2D.OπO has stemmed from the old but forgotten correlation between opioids consumption and metabolic trait abnormalities. Opioids classically act through delta opioid receptor (DOP encoded by OPRD1), kappa and mu opioid receptors. Based on my preliminary data that include large-scale human functional genetics of OPRD1 mutations, my hypothesis is that DOP is a major link between opioids and metabolism in humans. More specifically, I propose that DOP and opioid signaling have a crucial direct role in insulin secretion from pancreatic β cells; making DOP a promising new drug target against T2D.In this context, I suggest four tasks in OπO: the first two tasks will decipher the role of DOP and opioid signaling in metabolism with a specific focus on islets and β cells, while the two following tasks will decipher the systemic contribution of opioids and opioid receptors to metabolism. The methodologies that I proposed are truly comprehensive and innovative as they combine preclinical animal studies (with a humanized mouse model), deep phenotyping of islets, pharmacology, multi-omic analyses, genome editing, functional genetics, genetic epidemiology (including Mendelian randomization) and clinical intervention study. Fields of science medical and health sciencesmedical biotechnologygenetic engineeringgene therapymedical and health sciencesbasic medicinephysiologypathophysiologymedical and health sciencesclinical medicineendocrinologydiabetesnatural sciencesbiological sciencesgeneticsmutationmedical and health scienceshealth sciencesnutritionobesity Programme(s) HORIZON.1.1 - European Research Council (ERC) Main Programme Topic(s) ERC-2021-COG - ERC CONSOLIDATOR GRANTS Call for proposal ERC-2021-COG See other projects for this call Funding Scheme HORIZON-AG - HORIZON Action Grant Budget-Based Coordinator INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE Net EU contribution € 1 997 915,00 Address Rue de tolbiac 101 75654 Paris France See on map Region Ile-de-France Ile-de-France Paris Activity type Research Organisations Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00
