INSULIN RECEPTOR SUBSTRATE -1 AND FLUID SHEAR STRESS

（改编自申请人的摘要）拟议研究项目的目标 是：1）为心血管领域的职业生涯做好准备和培训候选人 为他提供必要的教育、环境和研究 支持，以及 2) 深入了解 IRS-1（胰岛素）的潜在作用 受体底物）在剪切应力诱导刺激的信号转导中 NO 产生和 TNF-α 对 IRS-1 信号传导的调节。 的 候选人将接受广泛的心血管教育 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 Ruedi Aebersold 和研究顾问委员会将监督 候选人的进展。 最后是医学系和医学部 心脏病学将全力致力于和支持发展 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 是一种多结构域胞质蛋白，在 胰岛素信号传输最近已被证明被多种使用 细胞因子、生长激素、白细胞介素和干扰素的受体。 我们有 获得了 IRS-1 在 FSS 机械传导中的初步数据 （流体剪切应力）在内皮细胞 NO 产生中。 该计划的主要目标是 研究计划是确定 IRS-1 的分子机制 这个背景。 II 型糖尿病在美国很流行，影响超过 5% 的人 的人口。 II 型糖尿病涉及胰岛素作用缺陷，如 以及胰岛素的分泌。 胰岛素抵抗是一种目标状态 细胞无法对正常水平的循环胰岛素作出反应；在 分子水平上，胰岛素受体 (IR) 或 IRS-1 的修饰可导致 到胰岛素抵抗。 TNF-α，增加丝氨酸磷酸化 IRS-1，减少胰岛素诱导的 IRS-1 酪氨酸磷酸化， IRS-1 的这种修饰最近被提议作为重要的调解者 胰岛素抵抗。 目前尚不清楚内皮细胞在葡萄糖中发挥重要作用 代谢和 IRS-1 在 FSS 内皮 NO 信号传导中的作用尚未明确 以前研究过。 我们实验室最近报告说 无生产中 FSS 的机械转导利用 P13 激酶依赖性 磷酸化 eNOS 的途径。 我们假设剪切应力诱导 NO 生产和胰岛素信号传导具有相同的重叠元素 信号通路和相同的对接蛋白 IRS-1 并且两条通路 受 TNF-α 调节，增加 IRS- 的丝氨酸磷酸化 1. 进一步表征胰岛素和 NO 之间的潜在联系 发信号。 具体目标 3：表征 FSS 相关信号元件 与 IRS-1 相关。

(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.