This is a renewal application for a program that will investigate the regulation and function of several genes known to be involved in pancreas function and development, and probably also discover new genes involved in these processes. The focus of the program will be the pancreatic beta cell, which plays an essential role in the pathophysiology of most diabetic diseases. All project leaders have a track record of productive collaborative interactions with investigators within this program, and elsewhere. The three projects within this program will be supported by four cores: Administrative, Mouse Husbandry and Genotyping, Pancreas Morphology, and Pancreas Bioinformatics. Project 2 (Magnuson) will determine the functional consequences of the lack of the type 1 sulfonylurea receptor (Sur1) on beta cell function and islet morphology. The reverse reaction of cre recombinase will be used to a ligand-inducible crePR fusion protein into the mouse insulin 1 gene locus and used to study the effects of acutely eliminating Sur1 in beta cells. Differences in the gene expression profiles of pancreatic islet neogenic precursor cells will be compared with that of pancreatic beta cells and delta cells using both suppression subtractive hybridization and DNA Microarray technologies. Project 3 (Stein) will isolate then clone the RIPE3b1 activator protein. Portions of the protein involved in transcriptional activation will be determined. Gene knockout mice will be generated using a cre-loxP gene targeting strategy protein in order to assess the role of this protein in pancreas development and function. Project 4 (Wright) will determine the effect of inactivating pdx-1 in specific embryonic endocrine and exocrine cells. The in vivo role of conserved cis-regulatory sequences in pdx-1 will be assessed. Lineage tracing techniques for a broad-based precise understanding of pancreatic cell ontogeny, particularly the endocrine pathway, will be developed.
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