Parathyroid Hormone-Related Protein and the Pancreatic Beta Cell

描述(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)，在几乎所有组织中表达，包括β细胞，是生命所必需的。来自我们团队和其他人的研究令人信服地证明，PTHrP在体外可以改善啮齿动物胰岛中的β细胞存活、功能和增殖。此外，我们发现PTHrP在体内具有类似的有益作用，当在使用大鼠胰岛素II启动子(RIP)的转基因小鼠的β细胞中过表达时。RIP-PTHrP转基因小鼠表现为胰岛增生，增强了β细胞的增殖、存活和功能，并导致高胰岛素血症和轻度低血糖。我们最近的数据表明，PTHrP(1-36)氨基末端区域的急性体内给药对正常小鼠的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可促进人β细胞的增殖，改善人的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，或PTHrP信号对正常β细胞生长和功能的生理作用，以及如何利用PTHrP的这些有利作用在治疗上促进胰岛功能、增殖和存活，人们知之甚少。这些都是贝塔细胞生物学领域需要解决的重要问题。考虑到目前全球糖尿病流行，胰岛移植作为糖尿病治疗方法的出现，目前可供移植的胰岛稀少，以及为未来治疗或预防糖尿病而需要进一步增强内源性β细胞的生长和功能，这一点尤其重要。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信号对于基础和/或应激诱导条件下的β细胞生长和/或功能是重要的，并且PTHrP对β细胞的这些积极作用可以用于治疗。因此，我们将以以下具体目标来解决这些目标：1)确定甲状旁腺素相关蛋白在体外增强β细胞功能、增殖和存活的信号通路(S)。2)确定PTH1R信号在体内对β细胞生长、功能和存活的生理作用。 3)研究PTHrP在胰岛移植结局中的作用。这些研究的结果将使我们更好地了解PTHrP是如何介导其对β细胞的有益影响的，它是一种前景广阔的β细胞生长因子，它的治疗潜力是否可以在胰岛移植的背景下被利用来改善胰岛的生长和功能，以及在未来用于内源性β细胞的再生，在预防和治疗糖尿病方面。公共卫生相关性：我们实验室和其他实验室的研究表明，甲状旁腺激素相关蛋白(PTHrP)作为一种β细胞生长因子具有巨大的前景，因为它可以增强β细胞的功能、增殖和存活。根据目前的提案进行的研究将揭开这种生长因子在正常条件下以及在1型和2型糖尿病的病理生理条件下介导其对β细胞的有益影响的机制。这将使我们能够为未来的治疗研究确定合适的分子靶点来改善胰岛的生长和功能。最重要的是，这些研究将检验PTHrP对β细胞的有益作用是否可以在治疗上被利用来改善胰岛移植。考虑到目前全球糖尿病流行，胰岛移植作为糖尿病治疗方法的出现，目前可用于移植的胰岛稀少，以及进一步加强内源性β细胞的生长和功能以用于未来治疗或预防糖尿病的需要，这些研究尤其重要。

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.