Diabetes mellitus is manifested as a reduction in insulin delivery required to maintain glucose homeostasis. A major goal in diabetes treatment is to re-establish metabolically regulated insulin secretion. Pancreatic beta cell replacement can serve as a means for metabolically regulated insulin delivery. One potentially renewable donor source of pancreatic beta cells needed for replacement therapies could be derived from human pancreatic ductal epithelial cells. Recently, the investigator's have been characterizing two human pancreatic ductule epithelial cell lines (HPDE-7 and HPDE-11 cells) transformed by expression of E6 and E7 gene of the human papilloma virus. Preliminary studies show that these cells form pancreatic ductule-like structures and express ductal cell genes when cultured on Matrigel. Importantly, when the ductule-like structures are cultured in hepatocyte growth factor and nicotinamide the cells synthesize and secrete insulin. Overall the investigators' studies suggest that HPDE cells are pluripotent cells capable of differentiating into either ductal cells or endocrine cells. The investigators' three specific aims are to: (1) characterize the defect that mitogens, differentiation agents, and extracellular matrix have on proliferation and differentiation of HPDE-7 and HPDE-11 cells in vitro; (2) examine whether transplantation of HPDE cells into different anatomical sites within alloxan-induced diabetic athymic mice has an effect on proliferation and differentiation of HPDE cells; (3) examine whether expression of transcription factors involved in beta cell development and maintenance can regulate HPDE cell proliferation and differentiation. Successful completion of these aims will develop a model for studying human beta cell neogenesis from pancreatic duct epithelial cells and may provide methods needed to generate a renewable source of transplantable human beta cell tissue.
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