Mechanisms to Induce Islet Proliferation

葡萄糖稳态主要是通过血糖调节、胰腺激素胰岛素和胰高血糖素的复杂平衡来维持的。1型糖尿病可抑制产生胰岛素的胰腺β细胞的自身免疫破坏。目前，治疗1型糖尿病的唯一方法是胰腺或胰岛移植，这些真正治愈方法的一个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，人们已经进行了大量的工作，目的是寻找胰岛素生成细胞的替代来源，以及建立刺激用于移植的胰岛增殖的方法。目前的应用解决了建立增加胰岛质量方法的关键需求。如果成功的话，所有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。我们最近发现抗胰岛蛋白酶肽三叶因子3 （TFF3）是胰岛的生长因子。

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.: