Gene Regulatory Signals for Beta Cell Development

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The goal of this proposal is to advance technologies and understanding about the mechanism of pancreatic beta cell development in embryogenesis and adult islets, and to promote the application of such advances to islet regeneration and stem cellbiology by other members of the Beta Cell Biology Consortium (BCBC). I propose to bring two technologies to the BCBC; one will identify new and unanticipated transcription factor-based regulatory events that are relevant to endocrine development, and the other will define endothelial cell signaling factors that promote endocrine differentiation and pancreatic stromal cell survival. In our first Aim, we will generate in vivo footprinting data and related information on pro- endocrine transcription factor genes at different stages ofpancreatic development and aging, to better define regulatory events that govern endocrine progenitor cell differentiation and beta cell regenerative capacity. By disseminating data to members of the BCBC, collaborators can help us define new factor- regulatory sequence interactions and use the information to monitor, predict, and ultimately perturb beta cell generation from stem cells and during islet regeneration. This approach is complementary to existing genetic studies, which give terminal phenotypes but not information about genetic regulatory mechanisms. In our second Aim, we will use existing endothelial cell lines and createnew ones from mouse embryos to identify endothelial signaling factors that promote endocrine progenitor differentiation and pancreatic stromal cell survival. Since endothelial cells and stromal cells both control pancreatic growth, these studies are intended to reveal new signaling molecules that control islet development and regeneration. Wealso plan to link Aims 1and 2by investigating transcription factor occupancies at pro-endocrine genes in response to endothelial signals. Bysharing technology and information from our work with the BCBC, our basic developmental studies will be more rapidly translated to develop cures for diabetes.