P9: REGULATION OF VSMC FUNCTION BY THE INSULIN SIGNALING PATHWAY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 糖尿病会增加心血管疾病的风险，其原因尚不清楚。使用药物洗脱支架输送雷帕霉素来抑制哺乳动物雷帕霉素靶点(MTOR)，并防止支架内再狭窄，表明mTOR在糖尿病条件下的作用发生了变化。本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(ERK1/2)。我们的假设是：在胰岛素抵抗的条件下，胰岛素刺激血管平滑肌细胞(VSMCs)会导致ERK活性增加，Akt活性降低，从而削弱mTOR通路在血管损伤反应中的作用。 我们将在三个目标上测试这一假设，目标是mTOR途径的不同水平。目的1将确定胰岛素抵抗是否降低mTOR在有丝分裂刺激下的激活，并测量其对该通路下游成分的影响。AIM 2将确定胰岛素抵抗条件下ERK1/2和Akt通路的激活。目标3将研究胰岛素受体、其接头蛋白以及连接Akt和ERK1/2活性的途径，以确定产生目标2中所见效应的机制。这些目标从mTOR激活开始，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。

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.