Hippocampal insulin signaling deficits in diabetic rats

糖尿病大鼠海马胰岛素信号缺陷

• 批准号: 7069020
• 负责人: LAWRENCE P REAGAN
• 金额: $ 31.39万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7069020
• 关键词: biological signal transduction; cognition; glucose transporter; hippocampus; insulin; insulin dependent diabetes mellitus; insulin receptor; laboratory rat; mitogen activated protein kinase; neuroendocrine system; neurophysiology; phosphatidylinositol 3 kinase; receptor expression

DESCRIPTION (provided by applicant): This proposal will examine the relationship between diabetes-mediated impairments in insulin receptor (IR) signal transduction mechanisms, including insulin-stimulated protein phosphorylation and glucose transporter (GLUT) trafficking, and the development of cognitive deficits in diabetic subjects. The hippocampus is an important integration center for learning and memory in the mammalian central nervous system (CMS) and is particularly sensitive and responsive to changes in insulin concentrations. Insulin administration improves cognitive performance in a variety of physiological and pathophysiological settings, including diabetes. Conversely, decreases in IR expression and/or signaling may contribute to the development of diabetic encephalopathy, including cognitive deficits observed in type 1 subjects. Unlike the peripheral IR system, little is known about the functional role of IRs in the CMS and how the activity of the neuronal IR system may be impaired in diabetes phenotypes. In view of the emerging relationship between insulin and cognition and the importance of the hippocampus in cognition, the aims of this proposal are: 1) to establish the functional relationships of components of the IR system in the rat hippocampus, including phosphatidylinositol 3-kinase (PI3-K), mitogen-activated protein kinase (MARK) signaling and the insulin-sensitive GLUTs; 2) to determine whether the neurological consequences of diabetes include impairments in IR expression and/or signaling; 3) to determine whether downregulation of IR expression in the rat hippocampus produces impairments in IR/PI3-K/MAPK signaling and GLUT trafficking, thereby providing a mechanistic basis for decreases in behavioral performance observed in experimental models of type 1 diabetes. Successful completion of these studies will: 1) determine the signal transduction mechanisms of the IR system in the brain; 2) provide insight into the mechanisms through which insulin enhances cognitive function in physiological settings; 3) provide a fundamental mechanistic bridge between impairments in IR expression and/or signaling and the morphological, electrophysiological and cognitive deficits associated with type 1 diabetes.

描述（由申请人提供）：该提案将研究糖尿病介导的胰岛素受体（IR）信号转导机制损伤（包括胰岛素刺激的蛋白质磷酸化和葡萄糖转运蛋白（GLUT）运输）与糖尿病患者认知缺陷的发展之间的关系科目。海马体是哺乳动物中枢神经系统（CMS）学习和记忆的重要整合中心，对胰岛素浓度的变化特别敏感和敏感。胰岛素给药可改善各种生理和病理生理环境（包括糖尿病）的认知能力。相反，IR表达和/或信号传导的减少可能导致糖尿病脑病的发展，包括在1型受试者中观察到的认知缺陷。与外周 IR 系统不同，我们对 IR 在 CMS 中的功能作用以及神经元 IR 系统的活性如何在糖尿病表型中受损的情况知之甚少。鉴于胰岛素与认知之间的新兴关系以及海马在认知中的重要性，本提案的目的是：1）建立大鼠海马IR系统各组成部分的功能关系，包括磷脂酰肌醇3-激酶（ PI3-K)、丝裂原激活蛋白激酶 (MARK) 信号传导和胰岛素敏感的 GLUT； 2) 确定糖尿病的神经系统后果是否包括IR表达和/或信号传导受损； 3) 确定大鼠海马中IR表达的下调是否会损害IR/PI3-K/MAPK信号传导和GLUT运输，从而为1型糖尿病实验模型中观察到的行为表现下降提供机制基础。成功完成这些研究将：1）确定大脑中IR系统的信号转导机制； 2）深入了解胰岛素在生理环境中增强认知功能的机制； 3) 在IR表达和/或信号传导损伤与1型糖尿病相关的形态学、电生理学和认知缺陷之间提供了一个基本的机制桥梁。