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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01DK080996-06
Application #
8694447
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Sato, Sheryl M
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Dhawan, Sangeeta; Georgia, Senta; Tschen, Shuen-Ing et al. (2011) Pancreatic ? cell identity is maintained by DNA methylation-mediated repression of Arx. Dev Cell 20:419-29
Dhawan, Sangeeta; Tschen, Shuen-Ing; Bhushan, Anil (2009) Bmi-1 regulates the Ink4a/Arf locus to control pancreatic beta-cell proliferation. Genes Dev 23:906-11