Parathyroid Hormone Related Protein in the Human Islet

描述(由申请人提供)： 随着最近胰岛移植作为治疗糖尿病的一种可行疗法的出现，了解人类胰岛生物学，从而找到改善人类β细胞功能、增殖、存活或分化的方法变得至关重要。这一点尤其重要，因为目前需要大量的胰岛来使糖尿病患者实现胰岛素独立，而且目前可供移植的胰岛数量很少。甲状旁腺激素相关肽(PTHrP)及其受体PTH1R通常在啮齿动物胰岛的β细胞中产生。PTHrP在转基因小鼠的β细胞中过表达会导致胰岛增生、低血糖和高胰岛素血症。此外，PTHrP在啮齿动物β细胞中过表达，使其对体内和体外多种刺激诱导的细胞死亡具有抵抗力。当外源性PTHrP多肽处理时，正常的小鼠β细胞也能抵抗细胞死亡。重要的是，PTHrP及其受体在人的胰岛中表达。然而，关于PTHrP在人胰岛中的表达或功能的位置还知之甚少。因此，这项建议的目的是确定PTHrP过表达对体外和体内移植环境中人胰岛增殖、功能和存活的影响。具体目标是： 1)检测PTHrP对体外培养的人胰岛细胞功能、增殖和存活的影响。 2)在链脲佐菌素诱导的糖尿病SCLD小鼠胰岛移植的最小质量模型中，确定PTHrP是否能改善人胰岛移植的结果。 这些研究将确定PTHrP是否可以在移植环境中改善人胰岛的增殖、存活和/或性能。这种性质的研究将是减少成功移植所需的胰岛数量的关键的第一步。

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.