Parathyroid Hormone Related Protein in the Human Islet

描述（由申请人提供）： 随着近年来胰岛移植作为治疗糖尿病的可行疗法的出现，了解人胰岛生物学并由此找到改善人β细胞的功能、增殖、存活或分化的方法变得至关重要。考虑到目前糖尿病患者需要大量的胰岛来引起胰岛素依赖性，以及目前可用于移植的胰岛的缺乏，这是特别重要的。甲状旁腺素相关肽（PTHrP）及其受体PTH 1 R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细胞中的过表达使它们对体内和体外由多种刺激诱导的细胞死亡具有抗性。当用PTHrP肽外源性处理时，正常小鼠β细胞也对细胞死亡具有抗性。重要的是，PTHrP及其受体在人类胰岛中表达。然而，关于PTHrP在人类胰岛中的表达或功能的位点知之甚少。因此，本建议的目的是确定PTHrP过表达对人胰岛增殖，功能和存活的影响，在体外和体内移植设置。具体目标是： 1)目的：研究甲状旁腺素相关蛋白（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是否可以改善人胰岛移植的结果。 这些研究将确定PTHrP是否可以改善移植环境中人类胰岛的增殖、存活和/或性能。这种性质的研究将是减少成功移植所需胰岛数量的关键第一步。

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.