Molecular Mechanisms of Human and Murine Beta Cell Proliferation and Regeneration

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DESCRIPTION (provided by applicant): The mission of the Beta Cell Biology Consortium (BCBC) is to generate functional human glucose-responsive, insulin-producing (-cells and to promote (-cell regeneration or proliferation of existing (-cells. While current research has identified many transcription factors and inductive signals that promote critical steps in mouse islet development, and that knowledge is guiding efforts to generate human beta cells from stem and progenitor cells, we have also learned that mouse and human islets differ significantly in terms of cellular composition, function, replication, regenerative capacity, and gene expression. These distinctive features of human islets and the need to translate emerging findings from rodent islet biology to human islets serve as the basis of our proposal. Our broad-based, interdisciplinary scientific team, consisting of experts in pancreatic islet and stem cell biology, islet regeneration, developmental biology, and "humanized" mice, will test the overall hypothesis that key genes and/or environmental stimuli which promote rodent (-cell proliferation can similarly induce the proliferation or regeneration of human or non-human primate (NHP) (-cells. We propose three specific aims: 1) Determine if signals that induce mouse (-cell proliferation also induce human and NHP (-cell proliferation in vivo and evaluate the effect of local inflammation on human and NHP (-cell proliferation. 2) Define the gene expression profile of proliferating human and NHP (-cells and build on these findings to induce proliferation of adult human (-cells. 3) Identify and characterize the regulators allowing and limiting postnatal islet (-cell proliferation in rodents, NHPs, and humans. Importantly, our investigative team will enhance the BCBC's team science-based efforts by: 1) focusing on human islet biology to complement and synergize with investigators working on either mouse pancreas and islet biology and/or human ES or iPS cells; 2) adding considerable expertise in the molecular mechanisms underlying (-cell development, cell fate determination, and proliferation; and 3) bringing and developing valuable research tools and technologies such as "humanized" mouse models, in vitro and in vivo models to study the proliferation and regeneration of fetal, juvenile, and adult human and NHP islets, and unique mouse models of (-cell proliferation and regeneration. PUBLIC HEALTH RELEVANCE: In both type 1 and type 2 diabetes, there are an insufficient number of insulin-producing cells. This interdisciplinary team is working to develop approaches to stimulate human insulin-producing cells to proliferate and regenerate as a new therapy for diabetes.