Regulation of Vascular Smooth Muscle Cell Proliferation

描述(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。糖尿病会增加致命的冠心病和外周血管疾病的风险。血管平滑肌细胞(VSMC)的增殖和迁移参与了冠状动脉疾病的发生，是心脏移植术后冠状动脉支架内再狭窄和加速病变的主要原因。药物洗脱支架(雷帕霉素-西罗莫斯)是治疗冠心病的一项重大进展，显著降低了再狭窄的发生率。然而，糖尿病患者的再狭窄发生率仍然是非糖尿病患者的两倍。我们将使用雷帕霉素作为“分子探针”来剖析调控VSMC生长和迁移的途径。目的一是验证糖尿病导致PI3K/Akt/FOXO通路过度刺激，降低p27Kip1基因表达，导致相对雷帕霉素耐药的假说。我们将观察雷帕霉素对高糖培养的VSMC增殖和迁移的影响，进而观察雷帕霉素对不同糖尿病模型小鼠动脉损伤后新生内膜增生的影响。目的二确定用雷帕霉素和Akt/PI3K抑制剂阻断多条生长通路是否能协同抑制糖尿病/肥胖动物模型血管损伤后的内膜增殖。我们将在动物模型中测试新药组合，在动物模型中观察到雷帕霉素的抗增殖作用。

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.