Parathyroid Hormone-Related Protein and the Pancreatic Beta Cell

描述（由申请人提供）：甲状旁腺激素相关蛋白（PTHrP）及其受体，甲状旁腺激素受体1 (PTH1R)，几乎在包括β细胞在内的所有组织中表达，是生命所必需的。我们和其他人的研究令人信服地证明，PTHrP可以提高体外啮齿动物胰岛中β细胞的存活、功能和增殖。此外，我们发现，当使用大鼠胰岛素II启动子（RIP）在转基因小鼠的β细胞中过表达时，PTHrP在体内具有类似的有益作用。RIP-PTHrP转基因小鼠表现出胰岛增生、β细胞增殖、存活和功能增强，并伴有高胰岛素血症和轻度低血糖。我们最近的数据表明，急性体内给药PTHrP（1-36）的氨基末端区域，PTH1R的配体，对正常小鼠的β细胞功能、增殖和β细胞质量有有益的影响。最重要的是，PTHrP促进人β细胞增殖，改善人β细胞功能。然而，尽管PTHrP对β细胞有多种积极作用，但关于PTHrP介导其有益作用的机制和信号通路知之甚少；或PTHrP信号传导对正常β细胞生长和功能的生理作用；或者如何利用PTHrP的这些有利作用来增强胰岛功能、增殖和存活。这些都是细胞生物学领域需要解决的重要问题。考虑到目前世界范围内的糖尿病流行，胰岛移植作为糖尿病治疗的出现，目前可用胰岛移植的缺乏，以及进一步增强内源性β细胞的生长和功能以治疗或预防糖尿病的需要，这一点尤为重要。根据我们的数据，我们假设PTHrP通过不同的信号通路介导其对β细胞的多种有益作用，β细胞中的PTHrP- pth1r信号传导对β细胞在基础和/或应激诱导条件下的生长和/或功能很重要，并且PTHrP对β细胞的这些多重积极作用可以用于治疗。因此，我们将通过以下具体目标来解决这些目标：1)确定PTHrP在体外增强β细胞功能、增殖和存活的信号通路。2)建立PTH1R信号在体内β细胞生长、功能和存活中的生理作用。

DESCRIPTION (provided by applicant): Parathyroid hormone-related protein (PTHrP), and its receptor, parathyroid hormone receptor 1 (PTH1R), expressed in almost every tissue including the beta cell, are required for life. Studies from our group and others, convincingly demonstrate that PTHrP improves beta cell survival, function and proliferation in rodent islets in vitro. Furthermore, we show that PTHrP has similar salutary effects in vivo, when overexpressed in beta cells of transgenic mice using the rat insulin II promoter (RIP). The RIP-PTHrP transgenic mice display islet hyperplasia, enhanced beta cell proliferation, survival, and function, with resultant hyperinsulinemia and mild hypoglycemia. Our recent data indicate that acute in vivo administration of the amino-terminal region of PTHrP(1-36), the ligand for the PTH1R, has salutary effects on beta cell function, proliferation and beta cell mass in normal mice. Most importantly, PTHrP enhances human beta cell proliferation and improves human beta cell function. However, despite the multiple positive effects of PTHrP on the beta cell, there is very little known regarding the mechanisms and signaling pathways through which PTHrP mediates its beneficial effects; or the physiological role of PTHrP signaling on normal beta cell growth and function; or how these favorable effects of PTHrP could be harnessed therapeutically to enhance islet function, proliferation, and survival. These are important issues that need to be addressed in the field of beta cell biology. This is especially critical given the current worldwide diabetes epidemic, the advent of islet transplantation as a treatment for diabetes, the current paucity of available islets for transplants, and the need to further enhance the growth and function of endogenous beta cells for the future cure or prevention of diabetes. Based on our data we hypothesize that PTHrP mediates its manifold salutary actions on the beta cell through distinct signaling pathways, that PTHrP-PTH1R signaling in the beta cell is important for beta cell growth and/or function either in basal and/or stress-induced conditions, and that these multiple positive effects of PTHrP on the beta cell can be harnessed therapeutically. Therefore, we will address these goals with the following Specific Aims: 1) To identify the signaling pathway(s) through which PTHrP enhances beta cell function, proliferation, and survival in vitro. 2) To establish the physiological role of PTH1R signaling in beta cell growth, function and survival in vivo. 3) To examine the role of PTHrP in islet transplant outcomes. Results from these studies should provide a better understanding of how PTHrP, a beta cell growth factor holding immense promise, mediates its beneficial effects on the beta cell, whether its therapeutic potential can be harnessed to improve islet growth and function in the context of islet transplantation, and in the future for regeneration of endogenous beta cells, in the prevention and cure of diabetes. PUBLIC HEALTH RELEVANCE: Studies from our lab and others have shown that parathyroid hormone-related protein (PTHrP) holds immense promise as a beta cell growth factor since it enhances function, proliferation, and survival of beta cells. Studies from the current proposal will unravel the mechanisms by which this growth factor mediates its beneficial effects in the beta cell both under normal conditions as well as under pathophysiological conditions of type 1 and type 2 diabetes. This will enable us to identify suitable molecular targets to improve islet growth and function for future therapeutic studies. Most importantly, these studies will examine whether the salutary effects of PTHrP on the beta cell can be harnessed therapeutically to improve islet transplants. These studies are especially critical given the current worldwide diabetes epidemic, the advent of islet transplantation as a treatment for diabetes, the current paucity of available islets for transplants, and the need to further enhance the growth and function of endogenous beta cells for the future cure or prevention of diabetes.