Friday, April 26, 2024
4/26/2024
Project Summary ß cell dysfunction is critical for the pathogenesis of type 2 diabetes mellitus (T2DM). Studies suggested that over-nutrition and inflammation induce profound changes in the transcriptome and the epigenome of beta cells, resulting in impaired glucose-stimulated insulin secretion, and loss of beta cell mass. However, the molecular mechanisms of the epigenetic regulation in beta cell function and failure remain largely unclear. Our recent results suggest that SIRT7, a NAD+-dependent deacetylase, regulate the glucose-stimulated insulin secretion (GSIS), and antagonize inflammation- and overnutrition-induced islet dysfunction. We found that SIRT7 activates the expression of a number of key genes in the insulin synthesis and secretion pathways, while suppresses the inflammatory and metabolic stress-induced transcription. These results raise the possibility that SIRT7 simultaneously activates GSIS pathway, and represses stress-induced inflammatory responses, through diverge molecular mechanisms. SIRT7 interacts with PBRM1, a chromatin remodeler, which controls the chromatin accessibility of regulatory cis-elements associated with the GSIS pathway genes. On the other hand, SIRT7 deacetylates H3K18Ac, a histone marks highly enriched in stress-induced promoter/enhancers in beta cells. In addition, the ability and specificity of SIRT7 to repress targets is regulated by the intracellular level of NAD+, and its interacting partner, vitamin D receptor (VDR), respectively. We hypothesize that SIRT7 is an essential regulator of insulin secretion and stress responses in beta cells through integrating NAD+ and vitamin D signaling at the chromatin level. Accordingly, Specific Aim 1 will utilize novel genetic loss-of-function mouse models to test the hypothesis that SIRT7 promotes insulin secretion through recruiting PBRM1 and maintaining the chromatin accessibility. Specific Aim 2 will use multiple diabetes mouse models, to determine the molecular underpinnings of SIRT7 in antagonizing stress-induced transcription in beta cells, through deacetylating H3K18Ac and acting as a novel co-repressor of VDR. Lastly, Aim 3 will dissect the converge of NAD+-SIRT7 and vitamin D-VDR signaling at the chromatin level, and test the therapeutic potential of co- activating SIRT7-VDR to antagonize both mouse and human islet dysfunction. The proposed project will reveal novel molecular regulatory mechanisms of beta cell function in healthy and dysfunctional state and may lead to novel strategies for the development of next generation anti-diabetic therapies directly targeting ß cell dysfunction.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
