Therapeutic approaches for diabetes involve restoring functional replacement of pancreatic beta cells from both endogenous and exogenous sources. Endogenous regeneration of beta cells has the potential to restore beta cell function using drug-based approaches, however pharmacologic agents that expand functional beta cell mass by safely promoting regeneration or expansion of endogenous beta cells have not been identified. Exogenous replacement of functional beta cells by islet transplantation has established proof of concept that restoration of functional beta cells has the potential to restore insulin independence. This success, however, is hampered by the lack of sufficient human donor cadaver pancreatic organs. This proposal is designed to address both of these limitations with a focus on filling a critical gap in validating a signaling pathway that can be manipulated by pharmacologic agents to regulate polycomb gene repression of Ink4a and promote endogenous expansion of beta cells. We have identified small molecule compounds that promote beta cell regeneration that work by inhibit TGF-beta signaling receptor ALK5. In this proposal we will establish the in vivo role of TGF-beta signaling in regulating beta cell replication using genetic mouse models that lack ALK5 in beta cells. We will tests the usefulness of small molecule inhibitors of the TGF-beta pathway to promote in vivo regeneration of human islets as well as improving islet transplantation outcomes. Pharmacologic agents that expand functional beta cell mass by safely promoting regeneration or expansion of endogenous beta cells may have clinical utility for the treatment of both type 1 and Type 2 diabetes in early stages of the disease and potentially in established disease.
As diabetic patients require life-long insulin therapy and have a high risk of medical complications, preventative or curative therapies are urgently needed. Diabetes results from an inadequate mass of functional beta cells and there is increasing evidence to suggests that replication of beta cell is the dominant means by which beta cells adapt to changing metabolic demands and during regeneration. This proposal is designed to address a critical gap in validating a signaling pathway that can be manipulated by pharmacologic agents to promote endogenous expansion of beta cells.
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