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: 7720716
• 负责人: Thomas Cooper Woods
• 金额: $ 16.58万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720716
• 关键词: Arteries; Atherosclerosis; Balloon Angioplasty; Blood Vessels; Cell physiology; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Condition; Coupled; Diabetes Mellitus; Disease; Equilibrium; Functional disorder; Funding; Grant; Inflammatory Response; Injury; Institution; Insulin; Insulin Receptor; Insulin Resistance; Insulin Signaling Pathway; Laboratories; Modeling; Molecular; Pathway interactions; Patients; Play; Population; Prevention; Process; Rate; Regulation; Research; Research Personnel; Resources; Role; Sirolimus; Smooth Muscle Myocytes; Source; Staging; Stents; Stimulus; Treatment Efficacy; United States National Institutes of Health; Vascular Diseases; arterial remodeling; diabetic; human FRAP1 protein; migration; prevent; response; response to injury; restenosis; vascular smooth muscle cell migration

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.

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