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Regulation of Vascular Smooth Muscle Cell Proliferation

血管平滑肌细胞增殖的调节

基本信息

批准号：
7816769
负责人：
Hana Totary-Jain
金额：
$ 5.38万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7816769
关键词：
1-Phosphatidylinositol 3-Kinase Accounting Address Amino Acids Animal Model Arterial Disorder Arterial Injury Back Binding Blood Vessels Cardiovascular Diseases Cause of Death Cell Shape Cell Size Cessation of life Chronic Clinical Trials Complement component C1s Coronary Arteriosclerosis Coronary artery Data Development Diabetes Mellitus Diabetic mouse Drug Combinations Eating Energy Metabolism Event Family Fatty Acids Feedback Figs - dietary GTP-Binding Proteins Gene Expression Glucose Growth Heart Transplantation Homologous Gene Hyperglycemia Hyperplasia In Vitro Incidence Injury Insulin Insulin Receptor Lead Leptin Malignant Neoplasms Measures Mediating Metabolic syndrome Mitogen-Activated Protein Kinases Modeling Molecular Probes Mus Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Nutrient Obesity Outcome PDPK1 gene PTEN gene Pathway interactions Peripheral Vascular Diseases Pharmaceutical Preparations Phosphatidylinositols Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Play Protein Kinase Protein Kinase C Proteins Proto-Oncogene Proteins c-akt Raptors Regulation Relative (related person)Resistance Ribosomal Protein S6 Kinase Risk Risk Factors Role Serine Severities Signal Pathway Signal Transduction Simulate Sirolimus Smooth Muscle Myocytes Somatomedins Stents Symptoms Tacrolimus Binding Protein 1A Tacrolimus Binding Proteins Testing Therapeutic Tuberous Sclerosis Tumor Suppressor Proteins United States Vascular Diseases cell growth diabetic diabetic patient feeding femoral artery glucose uptake human disease in vivo inhibitor/antagonist mTOR protein migration mouse model non-diabetic novel polypeptide prevent receptor restenosis tensin transcription factor vascular smooth muscle cell migration vascular smooth muscle cell proliferation

项目摘要

DESCRIPTION (provided by applicant): Cardiovascular disease accounts for nearly one third of deaths globally, and coronary artery disease remains the number one cause of death in the United States. Diabetes increases the risk of fatal CAD and peripheral vascular disease. Vascular smooth muscle cell (VSMC) proliferation and migration contribute to coronary artery disease and are the major causes of coronary artery in-stent restenosis and accelerated arteriopathy following cardiac transplantation. Drug-eluting stents (rapamycin-sirolimus) was a major advance in the treatment of CAD, causing significant reduction in the incidence of restenosis. However, diabetic patients still had a two-fold higher incidence of restenosis compared to non-diabetics. We will use rapamycin as a "molecular probe" to dissect pathways that govern VSMC growth and migration. Aim one will test the hypothesis that diabetes leads to an overstimulation of the PI3K/Akt/Foxo pathway', decreasing p27Kip1 gene expression, conferring relative rapamycin resistance. We will examine the effects of rapamycin on the proliferation and migration of VSMC grown in the presence of high glucose Jeptin treated, then on the formation of neointimal hyperplasia following arterial injury in different mouse models of diabetes. Aim two will determine whether blocking multiple growth pathways using rapamycin and inhibitors of Akt/PI3K can synergistically inhibit intimal proliferation following vascular injury in diabetic/obesity animal models. We will test new drug combinations in animal model in which resistance to rapamycin's antiproliferative effect was observed.

描述（由申请人提供）：心血管疾病占全球死亡人数的近三分之一，冠状动脉疾病仍然是美国的头号死因。糖尿病可增加致死性CAD和外周血管疾病的风险。血管平滑肌细胞（VSMC）的增殖和迁移与冠状动脉病变有关，是心脏移植后冠状动脉支架内再狭窄和加速动脉病变的主要原因。药物洗脱支架（雷帕霉素-西罗莫司）是治疗CAD的一项重大进展，可显著降低再狭窄的发生率。然而，糖尿病患者的再狭窄发生率仍然比非糖尿病患者高两倍。我们将使用雷帕霉素作为“分子探针”来剖析控制VSMC生长和迁移的途径。目的一是检验糖尿病导致PI 3 K/Akt/Foxo通路过度刺激，降低p27 Kip 1基因表达，赋予相对雷帕霉素抗性的假设。我们将研究雷帕霉素对高糖Jeptin处理的VSMC增殖和迁移的影响，然后在不同的糖尿病小鼠模型中动脉损伤后新生内膜增生的形成。目的二将确定使用雷帕霉素和Akt/PI 3 K抑制剂阻断多种生长途径是否可以协同抑制糖尿病/肥胖动物模型中血管损伤后的内膜增殖。我们将在动物模型中测试新的药物组合，在该模型中观察到对雷帕霉素的抗增殖作用的抗性。