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：
7406304
负责人：
Hana Totary-Jain
金额：
$ 5.03万
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/7406304
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 Condition 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 Numbers Nutrient Obesity Outcome PDPK1 gene PTEN gene Pathway interactions Patients 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 feeding femoral artery glucose uptake human disease in vivo inhibitor/antagonist 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的近三分之一，冠状动脉疾病仍然是美国死亡的第一大原因。糖尿病增加了致命CAD和周围血管疾病的风险。血管平滑肌细胞（VSMC）的增殖和迁移有助于冠状动脉疾病，是心脏移植后冠状动脉内再狭窄和加速动脉炎的主要原因。药物洗脱支架（雷帕霉素 - 丝洛木素）是治疗CAD的重大进步，导致再狭窄的发生率显着降低。但是，与非糖尿病患者相比，糖尿病患者的再狭窄发病率仍然高两倍。我们将使用雷帕霉素作为“分子探针”，以剖析控制VSMC生长和迁移的途径。 AIM ONE将检验糖尿病导致PI3K/AKT/FOXO途径的过度刺激的假设，从而降低了P27KIP1基因表达，从而赋予了相对雷帕霉素的耐药性。我们将检查雷帕霉素对在处理高葡萄糖的高糖素存在下生长的VSMC的增殖和迁移，然后在不同小鼠糖尿病模型中动脉损伤后新内膜增生的形成。目标两个将确定使用雷帕霉素和AKT/PI3K抑制剂阻断多个生长途径是否可以协同抑制糖尿病/肥胖动物模型血管损伤后内膜增生。我们将在动物模型中测试新药组合，其中观察到对雷帕霉素的抗增生作用的抗性。