IRS2 function in beta cell physiology

IRS2 在 β 细胞生理学中的功能

• 批准号: 7050416
• 负责人: Morris F. White
• 金额: $ 33.64万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7050416
• 关键词: NOD mouse; T lymphocyte; biological signal transduction; cell differentiation; cell proliferation; genetically modified animals; glucose metabolism; hormone regulation /control mechanism; insulin dependent diabetes mellitus; insulin receptor; insulin sensitivity /resistance; laboratory mouse; neuroendocrine system; noninsulin dependent diabetes mellitus; nutrient intake activity; pancreatic islet function; pancreatic islets; protein isoforms; protein protein interaction

DESCRIPTION (provided by applicant): This is a competing renewal of DK55326-05 entitled "IRS2 function in beta-cell physiology." During the past 5 years, our work established that the Irs2-branch of the insulin/IGF signaling cascade plays a central role in beta-cell growth, function and survival, especially during compensation for peripheral insulin resistance. Moreover, Irs2 signaling integrates hypothalamic nutrient sensing with peripheral insulin action to control nutrient homeostasis. Thus, partial dysregulation of Irs2 signaling in beta-cells and brain (hypothalamus) can explain the close association between obesity, peripheral insulin resistance, and beta-cell failure that characterizes type 2 diabetes. Diabetes is a major health problem around the world that develops when pancreatic beta-cells fail to secrete sufficient insulin quickly enough to maintain glucose homeostasis. Although polymorphisms in many genes are implicated in diabetes, dysregulation of the Irs2-signaling cascade-by environmental, metabolic or immunologic stress-can be a permissive step on the path to diabetes. Now our challenge is to understand the mechanisms that dysregulate Irs2 signaling in beta-cells and the hypothalamus, and determine how Irs2 signaling can be exploited to prevent obesity and cure diabetes. In this competing renewal, we propose four Specific Aims to investigate the crosstalk between Irs1 and Irs2 signaling cascades in beta-cell function and nutrient homeostasis, and explore strategies by which Irs2 signaling can be employed to promote beta-cell function and regeneration that prevents or cures diabetes: 1. Reveal the interaction between Irs1 and Irs2 signaling in nutrient homeostasis and beta-cell function. 2. Investigate the mechanism by which the common variant of IRS1 (G972Rlrs1) dysregulates beta-cell function and nutrient homeostasis in mice. 3. Establish the relation between T-cell infiltration and Irs2 signaling in beta-cells of the NOD mouse. 4. Investigate the mechanism of Irs2-dependent beta-cell regeneration.

描述（由申请人提供）：这是 DK55326-05 的竞争性更新，标题为“β 细胞生理学中的 IRS2 功能”。在过去的 5 年里，我们的工作确定了胰岛素/IGF 信号级联的 Irs2 分支在 β 细胞生长、功能和存活中发挥着核心作用，特别是在外周胰岛素抵抗的补偿过程中。此外，Irs2 信号传导将下丘脑营养感应与外周胰岛素作用相结合，以控制营养稳态。因此，β 细胞和大脑（下丘脑）中 Irs2 信号传导的部分失调可以解释肥胖、外周胰岛素抵抗和 2 型糖尿病特征的 β 细胞衰竭之间的密切关联。糖尿病是世界范围内的一个主要健康问题，当胰腺β细胞无法足够快地分泌足够的胰岛素来维持葡萄糖稳态时就会出现糖尿病。尽管许多基因的多态性与糖尿病有关，但环境、代谢或免疫应激导致的 Irs2 信号级联失调可能是导致糖尿病的一个允许因素。现在我们的挑战是了解β细胞和下丘脑中Irs2信号传导失调的机制，并确定如何利用Irs2信号传导来预防肥胖和治疗糖尿病。在这一竞争性更新中，我们提出了四个具体目标来研究 Irs1 和 Irs2 信号级联在 β 细胞功能和营养稳态中的串扰，并探索可利用 Irs2 信号传导促进 β 细胞功能和再生的策略，从而防止或阻止治疗糖尿病： 1. 揭示 Irs1 和 Irs2 信号在营养稳态和 β 细胞功能中的相互作用。 2. 研究 IRS1 (G972Rlrs1) 常见变体导致小鼠 β 细胞功能和营养稳态失调的机制。 3. 建立 NOD 小鼠 β 细胞中 T 细胞浸润与 Irs2 信号传导之间的关系。 4. 研究Irs2依赖性β细胞再生的机制。