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中枢神经系统和 胰岛素抵抗，肥胖的FA/FA Zucker大鼠。目标是增加 关于胰岛素受体和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 循环胰岛素能否激活中枢神经系统胰岛素受体。一个 最终目标是确定在任何 胰岛素抵抗Zucker胰岛素受体的信号活性 老鼠。 具体目标是： 1.确定胰岛素和IGF-1受体在细胞内的位置 和超微结构水平通过免疫细胞化学和相关性 发现含有磷酸酪氨酸的蛋白质的位置。 2.鉴定IGF-1受体的结构特征和 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 信令机制。 3.研究循环中的胰岛素引起反应的能力 在中枢神经系统。 4.评估胰岛素在中枢神经系统中的作用是否发生改变 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： 胰岛素受体和胰岛素样生长因子-I受体位于不同的神经元 人口。 IGF-I受体的β亚基存在两种异构体 可以产生一种混合受体。 这两种受体都通过酪氨酸激酶活性来增强 内源性底物酪氨酸磷酸化与PtdIns-3激酶 (类型1)。 循环胰岛素可直接激活中枢胰岛素受体。 肥胖的Zucker大鼠的胰岛素抵抗与 中枢神经系统酪氨酸激酶信号通路的缺陷 胰岛素受体。 这项工作的长期目标是理解 胰岛素和IGF-I在中枢神经系统功能调节中的作用

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.