INSULIN RECEPTOR SUBSTRATE -1 AND FLUID SHEAR STRESS

(改编自申请人的摘要)建议研究项目的目标 1)为心血管领域的职业生涯做好准备和培训 通过为他提供必要的教育、环境和 支持，以及2)深入了解IRS-1(胰岛素)的潜在作用 受体底物)在切应力刺激的信号转导中的作用 NO的产生和肿瘤坏死因子-α对IRS-1信号的调控。这个 应聘者将接受广泛的心血管方面的教育 生物化学、信号转导、生物物理学、研究方法和 统计数据。候选人将得到马歇尔·科森的支持和指导 以及鲁迪·埃伯索尔德，他将与研究咨询委员会一起监督 候选人的进步。最后，医学部和分部 心脏科将全心全意致力于发展 候选人作为独立调查员的职业生涯。拟议的研究 项目是实现这些目标的基础。 IRS-1是一种多结构域的胞浆蛋白，在 胰岛素信号传递，最近被证明被多个 细胞因子、生长激素、白介素类和干扰素的受体。我们有 获得的初步数据表明IRS-1参与FSS的机械转导 (流体切应力)在内皮细胞中产生NO。这次会议的主要目标是 研究建议是确定调控IRS-1的分子机制 这一背景。 II型糖尿病在美国很普遍，影响了超过5%的人 人口中的一部分。II型糖尿病涉及胰岛素作用缺陷，如 以及胰岛素的分泌。胰岛素抵抗是一种状态，目标是 细胞对正常水平的循环胰岛素没有反应；在 在分子水平上，胰岛素受体(IR)或IRS-1的修饰可以导致 对胰岛素抵抗的影响。增加丝氨酸磷酸化的肿瘤坏死因子-α 抑制胰岛素诱导的IRS-1酪氨酸磷酸化 IRS-1的这种修改最近被认为是一种重要的介体 胰岛素抵抗。 目前尚不知道内皮细胞在葡萄糖中扮演重要角色。 IRS-1在FSS内皮NO信号转导中的作用及代谢 以前研究过的。我们实验室最近报告说 NO产生中FSS的机械转导利用P13-激酶依赖 使eNOS磷酸化的途径。我们假设剪切力导致了NO 产生和胰岛素信号传递共享相同的重叠元素 信号通路和相同的对接蛋白IRS-1，并且这两个通路 是由增加IRS丝氨酸磷酸化的肿瘤坏死因子-α调节的。 1.进一步研究胰岛素和一氧化氮之间的这种潜在联系 发信号。具体目标3：表征依赖于FSS的信令元件 这与IRS-1有关。

(Adapted from applicant's abstract) The goals of the proposed research project are: 1) to prepare and train the candidate for a career in cardiovascular research by providing him with the necessary education, environment, and support, and to 2) to gain insight into the potential role of IRS-1 (insulin receptor substrate) in signal transduction of shear stress induced stimulation of NO production and the modulation of IRS-1 signaling by TNF-alpha. The candidate will be provided with extensive education in cardiovascular biochemistry, signal transduction, biophysics, research methods, and statistics. The candidate will be supported and mentored by Marshall Corson and Ruedi Aebersold who with the research advisory committee will monitor the candidate's progress. Finally, the Department of Medicine and Division of Cardiology will provide full commitment and support to developing the candidate's career as an independent investigator. The proposed research project is the foundation of attaining these goals. IRS-1 is a multi domain cytosolic protein that plays an important role in insulin signal transmission and has recently been shown to be used by multiple receptors for cytokines, growth hormones, interleukin and inteferons. We have obtained preliminary data implicating IRS-1 in mechanotranduction of FSS (fluid shear stress) in endothelial cell NO production. The major goal of the research proposal is to determine the molecular mechanisms regulating IRS-1 in this context. Type II diabetes is prevalent in the United States, affecting over 5 percent of the population. Type II diabetes involves defects in insulin action as well as insulin secretion. Insulin resistance is a state in which target cells fail to respond to ordinary levels of circulating insulin; at the molecular level, modifications in the insulin receptor (IR) or IRS-1 can lead to insulin resistance. TNF-alpha, which increases the serine phosphorylation of IRS-1, diminishes insulin induced tyrosine phosphorylation of IRS-1 and this modification of IRS-1 has recently been proposed as an important mediator of insulin resistance. Endothelial cells are not known to play a significant role in glucose metabolism and the role of IRS-1 in FSS endothelial NO signaling has not been previously studied. Our laboratory has recently reported that mechanotransduction of FSS in No production utilizes a P13-Kinase dependent pathway to phosphorylate eNOS. We hypothesize that shear stress induced NO production and insulin signaling share overlapping elements of the same signaling pathway and the same docking protein IRS-1 and that both pathways are modulated by TNF-alpha which increases the serine phosphorylation of IRS- 1. To further characterize this potential link between insulin and NO signaling. Specific Aim 3: Characterize FSS dependent signaling elements which associate with IRS-1.