Preservation and restoration of functional beta cell mass

描述(申请人提供)：功能性胰岛细胞群是通过增加分泌胰岛素的胰岛β细胞的大小和数量或破坏胰岛β细胞以及单个胰岛细胞的分泌能力的过程来调节的。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细胞质量的丧失。目前的应用解决了建立保护和/或恢复功能性β细胞团以对抗T2 DM的迫切需要。这项拟议工作的目标是确定可以用来刺激β细胞生长、促进β细胞存活、维持β细胞功能并最终恢复β细胞功能的途径。我们已经对β细胞增殖的“分子刹车”感兴趣，并热衷于证明这些刹车在贝塔细胞的生存和功能中也扮演着重要的角色。通过我们的工作，我们发现Mig6在β细胞应激过程中被诱导，它不仅损害β细胞的增殖，而且还诱导细胞凋亡。Mig6是一种抗增殖的内源性细胞，它既是增殖的分子刹车，又是支持生存的信号通路的刹车，我们推测消融Mig6将增加或至少保护体内功能性的β细胞质量。为此，提出了以下具体目标：1)确定Mig6如何在β细胞中废除促生存信号，2)证明Mig6如何在T2 DM的发展过程中调节功能性的β细胞质量，以及3)确定Mig6如何损害β细胞的功能。实验将在Beta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Beta细胞特异性缺失Mig6的小鼠模型中进行。这项拟议的工作将确定可用于预防或治疗T2 DM的治疗靶向的新途径。

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.