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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 糖尿病增加了心血管疾病的风险，原因尚不清楚。 使用携带雷帕霉素的药物洗脱支架抑制雷帕霉素（MTOR）的哺乳动物靶标，并预防静脉结构病，这表明在糖尿病条件下MTOR的作用改变了。 该项目将阐明胰岛素和胰岛素抵抗在改变MTOR抑制对损伤血管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（ERK1/2）。 我们的假设是：在胰岛素耐药条件下，通过胰岛素刺激血管平滑肌细胞（VSMC）导致ERK的激活增加，而AKT相对于正常VSMC，降低了AKT的激活，从而降低了血管对损伤血管反应中MTOR途径的作用。 我们将以三个目标来检验这一假设，以不同的水平MTOR途径。 AIM 1将确定胰岛素耐药性是否会响应有丝分裂刺激而降低MTOR的激活，并测量其对该途径下游成分的影响。 AIM 2将在胰岛素耐药条件下确定ERK1/2和AKT途径的激活。 AIM 3将检查胰岛素受体，其衔接蛋白以及连接AKT和ERK1/2活性的途径，以确定AIM 2中产生效果的机制。这些目的始于MTOR激活并向外移动以确定糖尿病如何改变其在对损伤的血管反应中的作用。