P9: REGULATION OF VSMC FUNCTION BY THE INSULIN SIGNALING PATHWAY

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。子项目及 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的研究机构。 该建议代表了我们实验室正在进行的努力的第二阶段，以阐明糖尿病患者血管疾病发病率增加背后的机制。 我们的研究重点是使用雷帕霉素（西罗莫司）洗脱支架预防支架内再狭窄，即球囊血管成形术后再狭窄与支架扩张，因为大规模临床试验已经证明这种治疗在糖尿病人群中的疗效降低。 这项工作的第一阶段已经确定，胰岛素抵抗在这种疗效丧失中起重要作用，并表明胰岛素刺激胰岛素受体途径（非同源）以外的途径的能力。 本研究旨在确定胰岛素在改变血管系统对雷帕霉素治疗的反应中的作用。 虽然我们关注的是支架内再狭窄，但这些研究对所有血管增生性疾病（例如动脉粥样硬化）的治疗都有意义，因为我们正在研究糖尿病的存在如何改变动脉对多种刺激反应的分子机制。 假设：在胰岛素抵抗条件下，胰岛素刺激IGFR途径更强烈地将ERK和Akt活性之间的平衡向ERK转移，并降低靶向mTOR途径预防支架内再狭窄的功效。 支架内再狭窄的过程与动脉粥样硬化的过程类似，尽管大大加速，并且通过Russell Ross的血管对损伤的反应模型描述。 简而言之，动脉的初始损伤（例如球囊血管成形术）导致内皮功能障碍和炎症反应。 这种炎症反应促使血管平滑肌细胞（VSMC）迁移到内膜并增殖形成新生内膜，导致管腔丢失和动脉重塑。 雷帕霉素通过抑制血管对损伤的反应中的VSMC增殖和迁移成分来阻断再狭窄。 该建议的策略是检查胰岛素对雷帕霉素在正常、胰岛素抵抗和2型糖尿病条件下调节血管对损伤的反应的能力的影响。

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. This proposal represents the second stage of the ongoing efforts in our laboratory to elucidate the mechanisms behind the increased rate of vascular diseases in patients with Diabetes Mellitius. We have focused our research on the use of rapamycin (sirolimus) eluting stents for the prevention of in-stent restenosis, the re-narrowing of an artery following balloon angioplasty coupled with the stent implantatin, as large scale clinical trials have demonstrated that the efficacy of this treatment is reduced in the diabetic population. The first stage of this effort has identified that insulin resistance plays an important role in this loss of efficacy and suggested a role for insulin's ability to stimulate pathways other than the insulin receptor pathway (non-cognate). The present studies are directed at determining insulin's role in altering the response of the vasculature to treatment with rapamycin. While we are focused on the in-stet restenosis, these studies have implications for the treatment of all vasculoproliferative diseases (e.g. atherosclerosis) as we are examining how the presence of diabetes alters the molecular mechanisms underlying arterial response to multiple stimuli. Hypothesis: Under insulin resistant conditions insulin stimulates the IGFR pathway more robustly shifting the balance between ERK and Akt activity towards ERK and diminishing the efficacy of targeting the mTOR pathway to prevent in-stent restenosis. The process by which in-stent restenosis proceeds in similar albeit greatly accelerated, to that fo atherosclerosis and is descrived by the vascular response to injury model of Russell Ross. In short, an initial injury to the arter (e.g. balloon angioplasty) leads to endothelial dysfunction and an inlammatory response. THis inflammatory response drives vascular smooth muscle cell (VSMC) migration to the intima and proliferation to form a neointima, resulting in lumen loss and arterial remodeling. Rapamycin blocks restenosis through inhibition of the VSMC proliferatino and migration component of the vascular response to injury. The strategy of this proposal is to examine the effects of insulin on rapamycin's ability to regulate the vascular response to injury under normal, insulin resistant, and type 2 diabetic conditions.