Preservation and restoration of functional beta cell mass

功能性β细胞团的保存和恢复

基本信息

批准号：
9330260
负责人：
Patrick T. Fueger
金额：
$ 28.9万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9330260
关键词：
Ablation Address Apoptosis Beta Cell Binding Biological Preservation Cell Death Cell Line Cell Proliferation Cell Survival Cell physiology Cellular Stress Data Deterioration Development Disease Epidermal Growth Factor Receptor Failure Financial compensation Functional disorder Genes Glucocorticoids Goals Growth Human Individual Insulin Insulin Resistance Insulin-Dependent Diabetes Mellitus Knowledge Laboratories MAPK8 gene MET gene Mediating Methods Molecular Mus Natural regeneration Non-Insulin-Dependent Diabetes Mellitus Oxidative Stress Pathway interactions Play Process Rattus Receptor Protein-Tyrosine Kinases Receptor Signaling Resistance Rodent Role Signal Pathway Signal Transduction Staging Structure of beta Cell of islet Testing Work cell growth combat endoplasmic reticulum stress functional loss functional restoration in vivo interest islet meetings mouse model novel nutrition overexpression prevent public health relevance research study response type I and type II diabetes

项目摘要

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.

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 型和 2 型糖尿病（分别为 T1DM 和 T2DM）的发生都需要功能性 β 细胞质量的丧失。当前的申请解决了建立保护和/或恢复功能性β细胞群以对抗T2DM的方法的迫切需要。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细胞的存活和功能中也发挥着重要作用。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 细胞增殖，而且诱导细胞凋亡。 Mig6 是一种内源性抗增殖药物，其作为增殖分子制动器的既定作用和作为促生存信号通路制动器的新兴作用，我们假设 Mig6 的消融将增加或至少保护体内功能性 β 细胞量。为此，提出以下具体目标：1) 定义 Mig6 如何消除 β 细胞中的促生存信号传导，2) 证明 Mig6 如何在 T2DM 的发展过程中调节功能性 β 细胞质量，以及 3) 确定 Mig6 如何在 T2DM 的发展过程中调节功能性 β 细胞质量。 Mig6 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细胞特异性删除Mig6的小鼠模型中进行。拟议的工作将确定可用于预防或治疗 T2DM 的新途径。