Mechanisms to Induce Islet Proliferation

葡萄糖稳态主要由葡萄糖调节激素胰岛素和胰高血糖素的复杂作用维持。1型糖尿病患者胰岛β细胞的自身免疫性破坏VT/H| ch产生胰岛素。目前，1型糖尿病唯一可用的治疗方法是胰腺或胰岛移植。这些真正的治疗方法的主要限制是来自尸体供体的胰腺和胰岛的有限可用性。由于这一瓶颈，人们进行了大量的工作，目的是寻找产生胰岛素的细胞的替代来源，以及建立刺激供移植的胰岛增殖的方法。本申请解决了建立增加胰岛质量的方法的迫切需要。如果成功的话，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。我们最近发现抗胰蛋白酶肽三叶因子3（TFF 3）是一种胰岛生长因子。 自从发现TFFS能够增加胰腺β细胞的细胞增殖以来，VT/E已经开始揭示导致这种有益效果的信号传导途径。然而，仍有许多工作要充分表征这些途径，并可能揭示其他途径，可以利用，以增加胰腺β细胞tmass。此外，继续识别能够增加β细胞质量的新因子也同样重要。为了实现这些目标，提出了以下具体目标：1）确定EGF1受体信号传导对TFF-3诱导的β细胞增殖的作用，2）确定基因33/Mig-6/RALT在调节EGF受体信号传导和β细胞增殖中的作用，和3）鉴定调节胰腺β细胞质量的新因子。这项工作的结果可能会增加islettrahsplant ^tlpn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.: