P9: REGULATION OF VSMC FUNCTION BY THE INSULIN SIGNALING PATHWAY

P9：胰岛素信号通路对 VSMC 功能的调节

• 批准号: 8168191
• 负责人: Thomas Cooper Woods
• 金额: $ 26.56万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168191
• 关键词: Adaptor Signaling Protein; Binding; Blood Vessels; Cell physiology; Computer Retrieval of Information on Scientific Projects Database; Diabetes Mellitus; Drug usage; Funding; Grant; Institution; Insulin; Insulin Receptor; Insulin Resistance; Insulin Signaling Pathway; Link; Measures; Pathway interactions; Phosphotransferases; Protein-Serine-Threonine Kinases; Regulation; Relative (related person); Research; Research Personnel; Resources; Role; Signal Transduction; Sirolimus; Smooth Muscle Myocytes; Source; Stents; Testing; United States National Institutes of Health; cardiovascular disorder risk; diabetic; mTOR protein; prevent; response; response to injury; restenosis

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Diabetes Mellitus increases the risk of cardiovascular disease and the reasons for this remain unclear. Use of drug eluting stents delivering rapamycin to inhibit the mammalian Target of Rapamycin (mTOR) and prevent in-stent restenosis has suggested an altered role for mTOR under diabetic conditions. This project will elucidate the role of insulin and insulin resistance in altering the effects of mTOR inhibition on the vascular response to injury. Insulin binds to the insulin receptor activating both the serine threonine kinase, Akt, and Extra-cellular Signal Regulated Kinases 1 and 2 (ERK1/2). Our hypothesis is: under insulin resistant conditions, stimulation of vascular smooth muscle cells (VSMCs) by insulin leads to increased activation of ERK and a decreased activation of Akt relative to normal VSMCs, diminishing the role the mTOR pathway in the vascular response to injury. We will test this hypothesis in three aims, targeting different levels of the mTOR pathway. Aim 1 will determine whether insulin resistance diminishes the activation of mTOR in response to mitogenic stimulation and measure its effects on downstream components of this pathway. Aim 2 will determine the activation of the ERK1/2 and Akt pathways under insulin resistant conditions. Aim 3 will examine the role of the insulin receptor, its adaptor proteins, and pathways linking Akt and ERK1/2 activity to determine the mechanism generating the effects seen in Aim 2. These aims start at mTOR activation and move outward to determine how diabetes alters its role in the vascular response to injury.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 糖尿病会增加心血管疾病的风险，其原因尚不清楚。 使用递送雷帕霉素的药物洗脱支架来抑制哺乳动物雷帕霉素靶蛋白（mTOR）并预防支架内再狭窄，表明mTOR在糖尿病条件下的作用改变。 该项目将阐明胰岛素和胰岛素抵抗在改变mTOR抑制对血管损伤反应的影响中的作用。 胰岛素与胰岛素受体结合，激活丝氨酸苏氨酸激酶Akt和细胞外信号调节激酶1和2（ERK 1/2）。 我们的假设是：在胰岛素抵抗条件下，相对于正常的血管平滑肌细胞（VSMC），胰岛素对血管平滑肌细胞（VSMC）的刺激导致ERK活化增加和Akt活化减少，从而降低了mTOR途径在血管对损伤的反应中的作用。 我们将从三个目标来测试这一假设，针对mTOR途径的不同水平。 目的1将确定胰岛素抵抗是否会减少mTOR对促有丝分裂刺激的激活，并测量其对该通路下游组分的影响。 目的2将确定在胰岛素抵抗条件下ERK 1/2和Akt通路的激活。 目的3将研究胰岛素受体的作用，其衔接蛋白，以及连接Akt和ERK 1/2活性的途径，以确定产生目的2中所见效应的机制。 这些目标从mTOR激活开始，并向外移动，以确定糖尿病如何改变其在血管损伤反应中的作用。