Preservation and restoration of functional beta cell mass

描述（由申请人提供）：功能性β细胞质量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型和2型糖尿病（分别为T1DM和T2DM）的发展都需要功能性β细胞质量的丧失。目前的应用解决了建立保护和/或恢复功能β细胞群的方法以对抗T2DM的关键需求。这项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细胞质量的途径。我们对β细胞增殖的“分子制动器”产生了兴趣，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Mig6在β细胞应激期间被诱导，它不仅损害β细胞增殖，而且诱导细胞凋亡。Mig6是一种抗增殖的内源性药物，其作为增殖的分子刹车和作为促生存信号通路的刹车的新作用已经建立，我们假设消融Mig6将增加或至少保护体内功能性β细胞质量。为此，我们提出了以下具体目标：1)确定Mig6如何消除β细胞中的促生存信号，2)证明在T2DM的发展过程中，Mig6如何调节功能性β细胞质量，3)确定Mig6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）和人类胰岛以及β细胞特异性缺失Mig6的小鼠模型中进行。这项工作将确定新的途径，以预防或治疗2型糖尿病。

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.