Mechanisms to Induce Islet Proliferation

血糖的稳定主要由糖代谢、胰岛素和胰升糖素的复杂平衡来维持。1型糖尿病患者首先依靠自身免疫破坏胰岛β细胞，Vt/h|ch产生胰岛素。目前，治疗1型糖尿病的唯一有效方法是胰腺或胰岛移植，真正有效的治疗方法之一是从身体捐赠者那里获得有限的胰腺和胰岛。由于这一瓶颈，许多工作已经完成，目标是找到一个天然的胰岛素产生细胞来源，并建立Riethpds来刺激胰岛的增殖，以利于移植。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，并摆脱这种严重的疾病。我们最近发现三叶因子3(TFF3)是一种胰岛生长因子。 自从TFFS促进胰岛β细胞增殖的能力被发现以来，Vt/e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的特征，并可能揭示其他可以被利用的途径，以便TB增加胰岛β细胞的分泌。此外，继续识别具有增加β细胞质量的作用的新因素也是同等重要的。为实现这些目标，我们提出了以下具体目标：1)确定EGF1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)寻找调节胰岛β细胞质量的新因素。这项工作的结果可能会增加岛叶植物的治疗效果。

Glucose hofrieostasis is prirharlly maintained by the intricate bsilance of the glucoregiilatory, pancreatic hormones insulin and glucagon. Type 1 diabetes meljitus resijlts fironn the autoimmune destruction of pancreatic beta cells vt/h|ch produce insulin. Currently, the onjy available cure for type 1 diabeties is pancreatic or iislet transplantation, A prihriary linnitatJbn of theise bona fide cures is the limited availability of pancreataand paricreatic islets from cadaver donors. Because of thjs bottleneck, much work has been perfonned with the goal of finding an aiternative source of insulin-producing cells as well as establishing riiethpds to stimulate proliferation bf islets harvissted for transplantation. The current application addresses the critical need to establish methods to increase pancreatic islet mass. If successful, nfiore patients with type 1 diabetes will benefit from islet transplantation and be free from this serious disease. We have recently discovered that the pf-btease-reslstant peptide trefoil factor 3 (TFF3) is a jgrpwth factor for pancreatic islets. Since the discovery of TFFS's ability to increase cell proliferation of pancreatic beta cells, vt/e 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 tb Increase pancreatic beta cell tmiass. Further, it is equallylmportantto continue to identify novel factors that have the abiJify to increase beta cell mass. In pursuit of these goals.the following specific aims are proposed: 1) to determine the role of EGFlreceptor signaling on TFF-3 induced beta cell proliferation, 2) to determine the ro\e of Gene 33/Mig-6/RALT in mbdulatlng EGF receptcr signaling and beta cell proliferation, and 3) to identify noverfactors that regulate pancreatic beta cell mass. The results of this work might increase the therapeutic efficacy of islettrahsplant^tlpn.: