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的竞争续约，标题为“ beta细胞生理学中的IRS2功能”。在过去的五年中，我们的工作确定，胰岛素/IGF信号传导的IRS2分支在β细胞生长，功能和生存中起着核心作用，尤其是在外围胰岛素抵抗的补偿期间。此外，IRS2信号传导将下丘脑营养感传感与周围胰岛素作用相结合，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，周围胰岛素抵抗和β细胞衰竭之间的紧密关联，而β细胞衰竭表征了2型糖尿病。糖尿病是世界上一个主要的健康问题，当胰腺β细胞无法迅速分泌足够的胰岛素以维持葡萄糖稳态时，它会发展出来。尽管许多基因中的多态性与糖尿病有关，但IRS2信号的环境，代谢或免疫应激 - can的失调是糖尿病路径的允许步骤。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信号传导以防止肥胖和治愈糖尿病。在这种竞争的续约中，我们提出了四个特定的目的，以研究IRS1和IRS2信号级联在β细胞功能和营养稳态中的串扰，并探索可以利用IRS2信号传导来促进beta细胞功能和再生的策略，以防止或治愈糖尿病： 1。揭示IRS1与IRS2信号传导之间的相互作用在养分稳态和β细胞功能中。 2。研究IRS1（G972RLS1）的共同变异的机制，使小鼠中的β细胞功能和营养稳态失调。 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细胞再生的机理。