The National Institute of Diabetes and Digestive and
Kidney Diseases (NIDDK) Website
PI Name: Deyu Fang, Ph.D.
Institution: University of Missouri School of Medicine
Project Number: DP2 DK083050-01
Project Title: Resveratrol: A Novel Target for Type 1 Diabetes
Type 1 diabetes (T1D) is particularly tragic because it usually starts in childhood and its effects worsen with time. This autoimmune disease is caused by self-attacking immune cells that result in the permanent destruction of the insulin-producing ß-cells in the pancreas. In healthy humans, most, if not all, self-attacking immune T cells are generally eliminated during development, and, if any leaking occurs, these cells are tolerized in the peripheral lymphoid tissues. Therefore, failing to induce the tolerance of T cells, which attach insulin-producing ß-cells, is crucial for type-1 diabetes. However, the molecular means by which T-cell tolerance is induced has remained an immunological puzzle for decades. Here we report that Sirt1, a type III histone deacetylase, is required for T-cell immune tolerance. Genetic disruption of Sirt1 function results in abnormally elevated immune responses and a break-down of T-cell peripheral tolerance. As a consequence, Sirt1-/- mice develop spontaneous autoimmunity. We have proposed that Sirt1-deficency may enhance diabetes development, and that
activation of Sirt1 by small molecules like resveratrol can potentially be used to treat type-1 diabetes by inhibiting ß-cell-attacking autoimmune T cells. Indeed, results from our preliminary studies indicate that resveratrol protects non-obesity diabetic mice from diabetes. A patent application for the use of Sirt1 activators in combating T1D in humans is currently being processed, and a manuscript describing our findings is under revision for publication by Cell. Therefore, this proposal aims to determine the molecular mechanisms underlying Sirt1 function as an anergic factor of T-cells, and to investigate how mis-regulated Sirt1 is involved in the development of T1D. We will also further examine the effects of resveratrol on preventing/treating T1D. Since FDA has approved the human use of resveratrol, we expect to develop a translational research program for the treatment of diabetes in humans with the support of this finding.
Public Health Relevance Statement: It is anticipated that this proposed research could resolve the immunological puzzle of T cell tolerance and result in potential therapeutic reagents for type 1 diabetes in humans.