This Program Project intends to collectively investigate in the individual characteristics, interactions, developmental interrelationships, and regulation of the four pancreatic islet cell types, which synthesize and secrete either glucagon (alpha cells), insulin (beta cells) , somatostatin (delta cells) , or pancreatic polypeptide (PP cells). Project 1 (Hanahan) will establish transgenic mice developing specific tumors of all four islet cell types, derive cell lines of each and study the expression of the four hormone genes in each cell type. The development of the islet cells will be studied with the goal of identifying the putative islet stem cell. CDNA libraries to each cell type will be produced and genes isolated that correlate with the common (unique) features of the islet cells and/or their development. Project 2 (Baekkeskov) will produce a 2D protein gel database for the four islet cell types, and compare them by various criteria. This section further intends t identify, isolate and clone the genes for beta-cell specific genes, and to clone cDNAs for two proteins which correlate with the maturation of the islets. Projects 2 and 3 will investigate cell adhesion and its involvement of cell organization within the islets an will seek to identify and characterize the cell adhesion molecules which are involved. Project 3 (Kelly) will study hormone secretion in the four islet cell types, with particular emphasis on the beta-cell. Two types of secretory dysfunctions will be studied those that arise in tumor cells, and those that effect diabetes in transgenic mice overexpressing MHC molecules on their beta-cells. Cell polarization will be examined in all four islet cells, as will development of their secretory capability during embryogenesis. Project 4 (Rutter) will examine the expression of known growth factor receptors an nuclear transcription factors in each cell type, and will seek to isolate the protein and clone the genes for the glucagon and somatostatin receptors, and to examine the mechanisms by which the different islet cells communicate so as to regulate each other's hormone gene expression. This project also intends (with Project 1) to isolate cDNAs of novel islet cell receptors and transcription factors. This Program Project will substantially increase our knowledge of the cell an molecular biology of the four islet cell types, and especially, the distinctive proper ties of the insulin-producing beta-cell, which is so remarkably susceptible to specific destruction and the consequent onset of insulin-dependent diabetes.
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