This is a Shannon Award providing partial support for the research projects that fall short of the assigned institute's funding range but are in the margin of excellence. The Shannon Award is intended to provide support to test the feasibility of the approach; develop further tests and refine research techniques; perform secondary analysis of available data sets; or conduct discrete projects that can demonstrate the PI's research capabilities or lend additional weight to an already meritorious application. The abstract below is taken from the original document submitted by the principal investigator. Insulin, the hormone that controls energy metabolism and regulates blood glucose levels, is produced exclusively in the beta-cells of the islets of Langerhans in the pancreas. When the amount of insulin supplied by the beta cells is inadequate for an individual's metabolic requirements, blood glucose levels rise and diabetes mellitus ensues. This laboratory studies the molecular biology of the beta-cell and the molecular pathology of diabetes mellitus. The long term objectives of this laboratory are to understand how the beta-cell regulates the expression of insulin and other key genes and to determine what underlying molecular defects in the beta-cell lead to diabetes mellitus. The work proposed in this grant application addresses the mechanism by which glucose and other nutrients regulate beta-cell gene expression. In the case of the insulin gene, a large part of this metabolic regulation is directed through upstream regulatory sequences (the promoter) and the nuclear proteins (transcription factors) that bind to these sequences.
The first aim of this proposal is to carefully delineate which beta cell promoters respond to glucose, what sequence within the promoters code for this response, and how these sequence elements interact. Next the proteins that bind these sites will be identified and characterized; and in some cases the genes that encode these factors will be isolated and cloned. The signaling pathways by which nutrient molecules regulate these elements will be dissected, with special emphasis on the calcium signaling pathway. An important aspect of this work is the use of normal beta-cells in primary islet cultures as opposed to aberrantly regulated tumor cell lines. This knowledge of gene expression in normal beta cells provides an unique opportunity to achieve our final aim, characterization of beta- cell gene expression in an animal model of non-insulin dependent diabetes (NIDDM). A wealth of evidence suggests that alterations in beta-cell gene expression may lead to the beta-cell defects seen in NIDDM, the most common form of diabetes mellitus in humans. The experiments proposed here will directly test this hypothesis. The information and reagents provided by these investigations will contribute ultimately to the understanding, treatment and cure of this devastating disease.
