Transcriptional regulation of pancreas development and function

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DESCRIPTION (provided by applicant): This is a competitive supplement in response to NOT-OD-09-058 (NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications). Diabetes is a metabolic disorder that currently affects over 180 million people worldwide. Common to all forms of diabetes is the gradual loss of functional insulin-producing ¿ cells in the endocrine pancreas. Thus, understanding the development, growth, survival and function of the endocrine pancreas may provide fundamental insight into treatments for this disease. Our studies have revealed that the Isl-1 transcription factor plays a crucial role in these processes in the endocrine pancreas. In our preliminary data, we show that a known Isl-1 co-regulator, Ldb1, is also required for the differentiation and/or function of endocrine cells. Thus, mutant mice lacking Ldb1 in the endocrine pancreas have no islet cells at 3 months of age and suffer from severe hyperglycemia. In contrary, mice with a germ-line deletion of closely related Ldb2 have no obvious phenotype. The effect of this Ldb1 mutant on islet cell formation is strikingly similar to our results with mice lacking Isl-1 in the endocrine pancreas. Based on these findings, we hypothesize that Ldb1 mediates Isl-1 action during islet cell development and in adult ¿ cell function. In a coordinated effort with Dr. Stein's laboratory at Vanderbilt University, we will 1) characterize Ldb1 and Ldb2 expression in the pancreas, 2) elucidate the role of Ldb1 in regulating endocrine cell development, and 3) examine how Ldb1 regulates adult ¿ cell function. CHOP contributes substantially to the local economy. In 2008, CHOP's operations created and supported over 16,882 jobs in the region, and CHOP's total economic impact was over $5.9 billion. Moreover, through a combination of private donations, NIH funding, and allocations from its hospital operations, CHOP receives more total research support than any other children's hospital in the United States--$180 million in fiscal year 2007-2008. This proposal will create four jobs (two at CHOP and two at Vanderbilt University). By doing so, funding this competitive supplement will expand the scope of my parent R01 and allow for job creation to improve our economy. PUBLIC RELEVANCE HEALTH: Diabetes mellitus is a metabolic disorder that current affects over 180 million people worldwide. Replacement of lost or improperly functioning ¿-cells represents the best possibility to cure, treat, or prevent diabetes. The experiments described in this application will help delineate the mechanisms controlling the growth and development of ¿-cells and bring us closer to generating functional ¿-cells for cell replacement therapy.