(Scanned from the applicant's description) Diabetes mellitus affects over 16 million individuals in the United States, resulting in substantial costs in morbidity, mortality, and health care expenditures. Current treatment regimens for diabetes mellitus do not normalize insulin production and/or action efficiently enough to restore normal glucose metabolism and prevent major vascular and neurologic complications of hyperglycemia. One approach to identify novel treatment strategies for diabetes mellitus is to study the regulation of insulin production and the molecular defects that lead to relative or absolute insulin deficiency. An increasing number of transcriptional regulators important for the development of the pancreas and/or the regulation of glucose-responsive insulin gene transcription are targets of mutations in individuals with maturity-onset diabetes of the young (MODY) or type 2 diabetes mellitus. Disrupting the functions of pancreatic beta-cell transcription factors may alter the regulation of islet cell mass, beta-cell function, or insulin gene transcription. Transcription factors essential for pancreatic development or for differentiated beta-cell function, including the regulation of insulin gene transcription, are candidate diabetes genes. We have identified a novel PDZ-domain protein, designated Bridge-1, that interacts with E2A transcription factors as a coactivator of insulin gene transcription. The proposed studies are designed to test the hypothesis that Bridge-1 is an important regulator of transcriptional activation of the insulin gene and a modulator of the function of key transcription factors and coactivators in pancreatic beta cells. To address this hypothesis, we propose the following specific alms: 1) to characterize Bridge-1 regulation of insulin gene transcription via protein-protein interactions in pancreatic beta cells, and 2) to determine whether overexpression of the coactivator Bridge-1 or a Bridge-1 transactivation mutant in pancreatic beta cells of transgenic mice alters insulin gene expression or the normal development of the endocrine pancreas. Because Bridge-1 appears to be an important transcriptional regulator of insulin gene expression we propose that it may be a promising candidate gene contributing to susceptibility for the development of type 2 diabetes mellitus.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Metabolism Study Section (MET)
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Margolis, Ronald N
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Massachusetts General Hospital
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Volinic, Jamie L; Lee, Jee H; Eto, Kazuhiro et al. (2006) Overexpression of the coactivator bridge-1 results in insulin deficiency and diabetes. Mol Endocrinol 20:167-82
Lee, Jee H; Volinic, Jamie L; Banz, Constanze et al. (2005) Interactions with p300 enhance transcriptional activation by the PDZ-domain coactivator Bridge-1. J Endocrinol 187:283-92