Mechanisms to Induce Islet Proliferation

描述(由申请人提供)： 血糖平衡主要由血糖调节、胰岛素和胰升糖素之间的复杂平衡来维持。1型糖尿病是产生胰岛素的胰岛β细胞自身免疫破坏的结果。目前，治疗1型糖尿病的唯一有效方法是胰腺或胰岛移植。这些真正的治疗方法的一个主要局限性是来自身体供者的胰腺和胰岛的可获得性有限。由于这一瓶颈，人们开展了大量工作，以期找到胰岛素产生细胞的替代来源，并建立刺激移植胰岛增殖的方法。目前的应用解决了建立增加胰岛质量的方法的迫切需要。如果成功，更多的1型糖尿病患者将从胰岛移植中受益，摆脱这一严重疾病。 我们最近发现，抗蛋白酶的三叶因子3(TFF3)是一种胰岛生长因子。自从发现转铁蛋白3的S能够促进胰岛β细胞的增殖以来，我们已经开始揭示导致这一有益效果的信号通路。然而，仍有许多工作要做，以充分描述这些途径，并可能揭示其他可以利用的途径，以增加胰岛β细胞质量。此外，继续识别具有增加β细胞质量能力的新因素也同样重要。为实现这些目标，我们提出了以下具体目标：1)确定EGF受体信号在TFF-3诱导的β细胞增殖中的作用；2)确定基因33/Mig-6/RALT在调节EGF受体信号和β细胞增殖中的作用；3)寻找新的调节胰岛β细胞质量的因子。 除了拟议的科学具体目标外，这项提议的另一个同样重要的目标是继续沿着成为独立调查人员的道路前进。这个奖项将是我追求糖尿病研究事业的最终目标的一个重要组成部分。

DESCRIPTION (provided by applicant): Glucose homeostasis is primarily maintained by the intricate balance of the glucoregulatory, pancreatic hormones insulin and glucagon. Type 1 diabetes mellitus results from the autoimmune destruction of pancreatic beta cells which produce insulin. Currently, the only available cure for type 1 diabetes is pancreatic or islet transplantation. A primary limitation of these bona fide cures is the limited availability of pancreata and pancreatic islets from cadaver donors. Because of this bottleneck, much work has been performed with the goal of finding an alternative source of insulin-producing cells as well as establishing methods to stimulate proliferation of islets harvested for transplantation. The current application addresses the critical need to establish methods to increase pancreatic islet mass. If successful, more patients with type 1 diabetes will benefit from islet transplantation and be free from this serious disease. We have recently discovered that the protease-resistant peptide trefoil factor 3 (TFF3) is a growth factor for pancreatic islets. Since the discovery of TFF3's ability to increase cell proliferation of pancreatic beta cells, we have begun to uncover the signaling pathways that lead to this beneficial effect. However, much work remains to fully characterize these pathways and to perhaps reveal other pathways that can be exploited in order to increase pancreatic beta cell mass. Further, it is equally important to continue to identify novel factors that have the ability to increase beta cell mass. In pursuit of these goals, the following specific aims are proposed: 1) to determine the role of EGF receptor signaling on TFF-3 induced beta cell proliferation, 2) to determine the role of Gene 33/Mig-6/RALT in modulating EGF receptor signaling and beta cell proliferation, and 3) to identify novel factors that regulate pancreatic beta cell mass. In addition to the proposed, scientific specific aims, an equally important aim of this proposal is to continue down the pathway of becoming an independent investigator. This award will be an instrumental component towards my ultimate goal of pursuing a career in diabetes research.