INSULIN AND IGF-I RECEPTORS IN THE CNS

拟议的研究将调查胰岛素和IGF-1的作用 和它们各自的受体在正常动物的中枢神经系统和 胰岛素抵抗肥胖fa/fa Zucker大鼠。 目标是增加 关于胰岛素受体位置的现有知识， IGF-1，它们提供生物信号的机制，以及 循环中的胰岛素是否能激活CNS胰岛素受体。 一 最终目标是确定是否存在异常， 胰岛素抵抗Zucker胰岛素受体的信号传导活性 大鼠 具体目标是： 1.确定胰岛素和IGF-1受体在细胞内的位置， 和超微结构水平的免疫细胞化学和相关性， 研究结果与磷酸酪氨酸蛋白的位置。 2. 描述IGF-1受体的结构特征， 评价胰岛素对酪氨酸激酶活性的影响， 内源性底物和潜在受体上的IGF-1受体 信号机制。 3. 研究循环胰岛素引起反应的能力 在CNS。 4. 评价胰岛素在中枢神经系统中的作用是否改变， 胰岛素抵抗、肥胖（fa/fa）Zucker大鼠。 这些具体目标将检验以下假设： i.胰岛素受体和IGF-I受体位于不同的神经元中， 人口。 ii. IGF-I受体的β亚基存在两种同种型， 可以产生一个混合受体。 iii.两种受体均通过酪氨酸激酶活性发出信号，以增强细胞的增殖。 内源性底物酪氨酸磷酸化和PtdIns-3激酶 (type 1）。 iv.循环胰岛素可直接激活CNS胰岛素受体。 v.肥胖Zucker大鼠的胰岛素抵抗与胰岛素抵抗相关。 缺陷的酪氨酸激酶信号通路， CNS 胰岛素受体 这项工作的长期目标是了解 胰岛素和IGF-I在调节CNS功能中的作用。

The proposed studies will investigate the actions of insulin and IGF-1 and their respective receptors in the CNS of normal animals and the insulin resistant, obese fa/fa Zucker rat. The goals are to add to existing knowledge on the location of the receptors for insulin and IGF-1, the mechanisms by which they provide biological signals, and whether circulating insulin can activate the CNS insulin receptor. A final goal is to determine if an abnormality exists in any of the signalling activities of the insulin receptor of insulin resistant Zucker rats. The specific aims are to: 1. Determine the locations of insulin and IGF-1 receptors at the cellular and ultrastructural levels by immunocytochemistry and correlate the findings with the location of phosphotyrosine containing proteins. 2. Characterize the structural features of the IGF-1 receptor and evaluate the effects of tyrosine kinase activities of the insulin and IGF-1 receptors on endogenous substrates and on potential receptor signaling mechanisms. 3. Investigate the ability of circulating insulin to elicit a response in the CNS. 4. Evaluate whether the actions of insulin are altered in the CNS of insulin resistant, obese (fa/fa)Zucker rats. These specific aims will test the following hypotheses: i.Insulin receptors and IGF-I receptors are located in different neuronal populations. ii.Two isoforms exist for the beta subunit of the IGF-I receptor which can generate a hybrid receptor. iii.Both receptors signal via tyrosine kinase activity to enhance the tyrosine phosphorylation of endogenous substrates and PtdIns-3 kinase (type 1). iv.Circulating insulin can directly activate the CNS insulin-receptor. v. The insulin resistance of obese Zucker rats is associated with a defect in the tyrosine kinase signaling pathway for the CNS insulin receptor. The long-term goal of this work is to understand the roles for insulin and IGF-I in the regulation of CNS function.