NEW BETA CELL-SPECIFIC MEMBRANE PROTEIN RELEVANT TO IDDM

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Insulin-dependent diabetes mellitus is a common, potentially lethal disease that strikes approximately 1 in 10,000 children under the age of 20 in the United States each year. The cause of this disease is an absolute, irreversible loss of the insulin-producing beta cells of the pancreatic islets, but, the mechanism of the destruction of the beta cells is unknown. Many lines of evidence have pointed to autoimmunity as the most likely cause of the beta cell loss. The most consistent finding in this juvenile form of diabetes is the presence of autoantibodies against the islet cells. There has been difficulty in taking advantage of these islet cell antibodies to study the mechanism of diabetes as they are believed to bind to a number of different auto- antigens whose structure and properties are incompletely known. More- over, the functions of these autoantigenic substances are also largely unknown. We have discovered a mouse monoclonal antibody that binds to the same antigen on rat beta cells that most children with diabetes also make autoantibodies to. We have learned that these antibodies bind to a membrane protein that is found only in the beta cells of the pancreas. Protein is large with a molecular weight of approximately 150,000. We have also been able to isolate messenger RNA from the pancreas which can synthesize this protein in vitro. We propose to take advantage of the discovery of this monoclonal antibody and this novel beta cell protein to understand the structure of the protein and its gene, to explore the possible functional roles for the protein and the regulation of its expression in the normal beta cell, to determine whether this protein might serve as a target for the cell-mediated arm of the immune system which has been shown to be responible for beta cell killing in the animal models of insulin-dependent diabetes, and, lastly, to ascertain whether differences in the gene for this protein may contribute to the genetic susceptibility for diabetes.