Parathyroid Hormone Related Protein in the Human Islet

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DESCRIPTION (provided by applicant): With the recent advent of islet transplantation as a feasible therapy for the treatment of diabetes, understanding human islet biology and thereby finding means to improve function, proliferation, survival or differentiation of human beta cells becomes vital. This is especially crucial given the large number of islets required at present to cause insulin-independence in a diabetic patient, as well as the paucity of islets currently available for transplantation. Parathyroid hormone-related peptide (PTHrP) and its receptor, PTH1R, are normally made in the beta cells of rodent islets. Overexpression of PTHrP in the beta cell of transgenic mice causes islet hyperplasia, hypoglycemia and hyperinsulinemia. Furthermore, PTHrP overexpression in rodent beta cells makes them resistant to cell death induced by multiple stimuli both in vivo and in vitro. Normal mouse beta cells are also resistant to cell death when treated exogenously with PTHrP peptide. Importantly, PTHrP and its receptor are expressed in human islets. However, there is very little known regarding the site of expression or function of PTHrP in human islets. Thus, the goal of this proposal is to determine the effect of PTHrP overexpression on human islet proliferation, function and survival in vitro and in vivo in a transplant setting. The Specific Aims are: 1) To examine the effect of PTHrP on the function, proliferation and survival of human islet cells in vitro. 2) To determine whether PTHrP can improve human islet transplant outcomes in a minimal mass model of islet transplantation in streptozotocin-induced diabetic SClD mice. These studies will determine whether PTHrP can improve proliferation, survival and/or performance of human islets in a transplant setting. Studies of this nature would be a critical first step towards reducing the number of islets required for successful transplantation.