Preservation and restoration of functional beta cell mass

描述（由申请人提供）：功能性β细胞群通过增加分泌胰岛素的胰腺β细胞的大小和数量或破坏β细胞以及单个β细胞的分泌能力的过程来调节。1型糖尿病和2型糖尿病（分别为T1 DM和T2 DM）的发生都需要功能性β细胞质量的损失。本申请解决了建立保护和/或恢复功能性β细胞群以对抗T2 DM的方法的关键需求。拟议工作的目标是确定可用于刺激β细胞生长，促进β细胞存活，维持β细胞功能并最终恢复功能性β细胞群的途径。我们对β细胞增殖的“分子制动器”感兴趣，并热衷于证明这些制动器在β细胞存活和功能中也起着重要作用。通过我们的工作，我们发现Mig 6在β细胞应激期间被诱导，其中它不仅损害β细胞增殖，而且诱导凋亡。Mig 6是一种抗增殖内源性物质，其作为增殖的分子制动器的既定作用和作为促存活信号传导途径的制动器的新兴作用，我们假设Mig 6的消融将增加或至少保护体内功能性β细胞群。为此，提出了以下具体目标：1）确定Mig 6如何消除β细胞中的促存活信号传导，2）证明Mig 6如何在T2 DM发展过程中调节功能性β细胞群，3）确定Mig 6如何损害β细胞功能。实验将在β细胞系（必要时）、分离的啮齿动物（大鼠和小鼠）和人胰岛以及Mig 6 β细胞特异性缺失的小鼠模型中进行。拟议的工作将确定新的途径，而不是可以治疗靶向预防或治疗T2 DM。

DESCRIPTION (provided by applicant): Functional beta cell mass is regulated by processes that either increase the size and number of insulin- secreting pancreatic beta cells or destroy beta cells as well as the secretory capacity of individual beta cells. A loss of functional beta cel mass is required for the development of both type 1 and type 2 diabetes mellitus (T1DM and T2DM, respectively). The current application addresses the critical need to establish methods to protect and/or restore functional beta cell mass to combat T2DM. The goals of the proposed work are to identify pathways that can be exploited to stimulate beta cell growth, promote beta cell survival, maintain beta cell function, and ultimately restore functional beta cell mass. We have become interested in "molecular brakes" for beta cell proliferation and are keen to demonstrate that these brakes also play an important role in beta cell survival and function. Through our work we discovered that Mig6 is induced during beta cell stress where it not only impairs beta cell proliferation but also induces apoptosis. Mig6 is an anti-proliferative endogenous its established roles as a molecular brake for proliferation and emerging role as a brake for pro- survival signaling pathways, we hypothesize that ablation of Mig6 will increase or at least protect functional beta cell mass in vivo. To this end, the following specific aims are proposed: 1) to define how Mig6 abrogates pro-survival signaling in the beta cell, 2) to demonstrate how Mig6 regulates functional beta cell mass during the development of T2DM, and 3) to establish how Mig6 impairs beta cell function. Experiments will be conducted in beta cell lines (when necessary), isolated rodent (rat and mouse) and human islets, and a mouse model of beta cell-specific deletion of Mig6. The proposed work will identify new pathways than can be therapeutically targeted to prevent or treat T2DM.