Role of IGF-1 and insulin receptors beta-cell survival

项目总结/摘要 1型糖尿病和2型糖尿病的主要特征是缺乏功能性胰岛细胞， 胰岛生物学中的紧迫问题与胰岛细胞群的可塑性有关， 制定治疗这两种疾病的策略。此应用程序的重点是 生长因子的作用，特别是胰岛素和IGF-I受体和蛋白质在其信号传导中的作用 途径，调节细胞增殖、凋亡和分泌功能。我们使用 在胰岛素/IGF-I信号传导中缺乏一种或多种蛋白质的独特遗传小鼠模型 细胞中的通路，并补充在细胞系和原代胰岛中的研究 用于体外和离体实验。根据我们寻求的数据， 继续我们的研究与以下具体目标：目标1：确定的作用， 胰岛素/IGF-I信号在胰岛素原加工中的作用，并检验一个完整的 胰岛素/IRS-2通路对于适当的胰岛素原加工是必需的。目标2：定义 胰岛素缺乏蛋白质的细胞中内质网（ER）应激的改变 胰岛素/IRS-2信号通路是限制胰岛素分泌的关键。 细胞中的内质网应激：我们的初步数据表明胰岛素受体的直接作用， IRS-2，而不是IRS-1，在内质网应激反应中的细胞。我们计划剖析 以及胰岛素/IRS-2信号传导背景下增强的ER应激的基础途径 重点是IRE-1a，并将这些发现与IRS-1介导的途径进行对比。目的 3：剖析胰岛素/IGF-I信号传导与参与胰岛素抵抗的蛋白质之间的联系机制。 胰岛素抵抗的细胞生长反应：我们使用体内方法的初步数据 建立在以前的工作，并指出细胞周期蛋白D2和Px-1的关键作用， 胰岛素抵抗的代偿性胰岛生长反应。我们将重点关注这两个 蛋白质，并探索它们与FoxO 1的联系，以剖析 增殖反应，特别是在胰岛素和IGF-1之间差异的背景下 发信号。目的4：确定胰岛增生小鼠模型中的胰岛和胰岛细胞蛋白质组 重点是鉴定参与细胞增殖和抗凋亡的新蛋白质。 我们相信，这些研究将为生长因子在肿瘤生长中的作用提供新的见解。 调节细胞增殖和凋亡。

Project Summary/Abstract A paucity of functional ¿-cells is a central feature of type 1 and type 2 diabetes and an urgent question in islet biology relates to plasticity of ¿-cell mass in the long-term goal of developing strategies to treat both forms of the disease. This application is focused on the role of growth factors, especially insulin and IGF-I receptors and proteins in their signalling pathway, in regulation of ¿-cell proliferation, apoptosis and secretory function. We use unique genetic mouse models lacking one or more proteins in the insulin/IGF-I signalling pathway in ¿-cells and complement with studies in ¿ cell lines and primary islets derived from the knockouts for in vitro and ex vivo experiments. Based on Preliminry Data we seek to continue our studies with the following Specific Aims: Aim 1: Determine the role of insulin/IGF-I signaling in proinsulin processing and test the hypothesis that an intact insulin/IRS-2 pathway is essential for appropriate proinsulin processing. Aim 2: Define the alterations in endoplasmic reticulum (ER) stress in ¿ cells lacking proteins in the insulin signaling pathway and test the hypothesis that the insulin/IRS-2 pathway is essential to limit ER stress in ¿ cells: Our preliminary data indicates a direct role for the insulin receptor and IRS-2, but not IRS-1, in ER stress responses in ¿ cells. We plan to dissect the mechanisms and pathways that underlie enhanced ER stress in the context of insulin/IRS-2 signaling with a focus on IRE-1a and contrast the findings with the pathways mediated by IRS-1. Aim 3: Dissect the mechanisms that link the insulin/IGF-I signaling with proteins involved in the ¿-cell growth response to insulin resistance: Our preliminary data using in vivo approaches builds on previous work and indicates critical roles for cyclin D2 and Px-1 in the compensatory islet growth response to insulin resistance. We will focus on these two proteins and explore their link with FoxO1 to dissect the mechanisms that underlie the proliferation responses especially in the context of differences between insulin and IGF-1 signaling. Aim 4: Define the islet and ¿-cell proteome in mouse models of islet hyperplasia with a focus on identifying novel proteins involved in ¿-cell proliferation and anti-apoptosis. Together we believe thee studies will provide novel insights into the role of growth factors in the regulation of ¿-cell proliferation and apoptosis.