Failure of pancreatic beta cells to maintain adequate functional capacity leads to increasing blood glucose levels and subsequent type 2 diabetes (T2DM). This disease imposes a huge, and growing, socio-economic burden on European and global societies. However, the pathophysiological mechanisms underlying beta cell dysfunction remain poorly understood, limiting the availability of novel approaches to treat or prevent T2DM. Here, we propose an Integrated Project that will lead to an unprecedented understanding of the factors influencing the maintenance (and loss) of normal beta cell functional capacity. This will be realized through the application of functional genomics technologies in an integrated and systematic approach, which employs studies in cellular and animal models as well as genetic analysis of human monogenie and polygenic T2DM patients. The project will integrate leading European experts in islet diabetes research, human geneticists, bioinformaticians and computational scientists as well as SMEs. Specific aims will be to: - Dissect the molecular pathways and identify key regulatory events - including those contributed by tissues located outside the endocrine pancreas - that control the ability of the beta cell to maintain its secretory function over a lifetime. - Identify key pathophysiological events in the above pathways that become dysfunctional in T2DM and determine the contributions of lipotoxicity, glucotoxicity, oxidative stress and me impact of genetic variations in the induced beta cell dysfunction. - Select genes and proteins that are candidates in the pathogenesis of beta cell dysfunction and assess their physiological role and potential value as novel drug targets for prevention and treatment of T2D. Collectively this program will lead to an unprecedented understanding of beta cell molecular physiology and pathophysiology to pave the way for improved health in Europe.
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