MMPC :: MICROMouse Program Application Abstract

MICROMouse Program Application Abstract

MMPC Funded Abstracts

MICROMouse

Funding Programs

Effects of acute deletion of selective transcription factors on mouse islets

Craig Nunemaker (Athens, OH)

MICROMouse Program

A key component of many metabolic diseases including diabetes is the dysfunction and eventual death of pancreatic islets of Langerhans, which are tissues that produce and secrete peptides that are important for regulating blood sugar and energy. Our specific interest is maturity-onset diabetes of the young (MODY), a group of single-gene disorders in humans that have been successfully modeled in mice through induced mutations. In human, MODY is generally apparent before age 25 due to an inability to make enough insulin to properly regulate blood sugar. Most forms of MODY are caused by defects in transcription factors. These transcription factors control whether or not certain genes are activated, and they appear to form a transcriptional network needed for normal pancreatic islet function. We are interested in transcription factor HNF-1alpha, which is responsible for MODY type 3 (MODY 3) and expressed in several gut tissues including liver, kidney, intestine, and endocrine pancreas. Clinical studies in humans have shown that mutations in HNF-1alpha are associated with impaired insulin secretion and reduced pancreatic islet function. In this proposal, we will apply a recently developed approach using small interference RNA (siRNA) to cause an acute and tissue-targeted reduction of HNF-1alpha protein in pancreatic islets. The goal is for this technique to provide a generalized approach to the study of either KO or transgenic mouse models. By temporarily knocking down HNF-1alpha in islets, we will be able to examine the role of HNF-1alpha in pancreatic islet function during (1) normal conditions and (2) under metabolically stressful conditions related to diabetes. Dr. Craig Nunemaker (University of Virginia) developed a series of in vitro tests using MMPC funds from a P&F project that chiefly uses fluorescent imaging techniques to better compare islet function from different mouse models. Dr. Gary Cline directs the MMPC Analytical Core at Yale University, which provides isotopic and chemical analysis of metabolites used to characterize physiologic parameters of metabolic flux rates, substrate turnover, and targeted metabolomics assays on mitochondrial anapolerosis. These investigators will apply their respective skills toward a common purpose in understanding the role of transcription factor HNF-1alpha in pancreatic islet function in mouse models of diabetes.

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