Over the first five years of funding of this program project grant (PPG), our laboratory has beenapplying an interdisciplinary approach for defining metabolic abnormalities of liver, pancreatic isletbeta-cells, and skeletal muscle in diabetes and obesity. Over the same time period, other members ofthis PPG team have developed technologies for functional imaging, targeted delivery of genes andother molecular cargo, and customized gene activation switches. The most compelling advancesmade by the PPG team have occurred in the area of pancreatic islet biology and related technologies.We have therefore chosen to focus the competitive renewal of this application on development of newstrategies for understanding and reversing beta-cell dysfunction of type 2 diabetes. The goal of thisproject (Project 1) is to investigate and validate novel pathways for control of beta-cell function and growththat have emerged from our work in the prior funding period. The project will make extensive use ofextraordinary technologies resident in Core B for beta-cell specific gene delivery in adult animals, and inCore C for comprehensive MS- and NMR-based metabolic analysis of islets and beta-cell lines.
The specific aims of the project are: 1) To investigate mechanisms by which manipulation of thehomeodomain transcription factor Nkx6.1 and its target genes affect glucose-stimulated insulinsecretion (GSIS) in pancreatic islets; 2) To investigate mechanisms by which manipulation of thehomeodomain transcription factor Nkx6.1 and its target genes affect pancreatic islet growth; 3) To testthe potential protective or restorative effect of Nkx6.1 and its target genes in preservation of beta-cellmass and function in cellular and animal models of type 2 diabetes.
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