Regulation of Vascular Smooth Muscle Cell Proliferation

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亡原因。糖尿病增加了致命性冠心病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病变，是心脏移植后冠状动脉支架内再狭窄和动脉病变加速的主要原因。药物洗脱支架（雷帕霉素-西罗莫司）是治疗冠心病的主要进展，可显著降低再狭窄的发生率。然而，与非糖尿病患者相比，糖尿病患者的再狭窄发生率仍然高出两倍。我们将使用雷帕霉素作为“分子探针”来解剖控制VSMC生长和迁移的途径。第一个目标将测试糖尿病导致PI3K/Akt/Foxo通路过度刺激的假设，降低p27Kip1基因表达，赋予相对雷帕霉素抗性。我们将在不同的糖尿病小鼠模型中研究雷帕霉素对高糖Jeptin处理下生长的VSMC增殖和迁移的影响，以及对动脉损伤后新生内膜增生的影响。目的二将确定在糖尿病/肥胖动物模型中，使用雷帕霉素和Akt/PI3K抑制剂阻断多种生长途径是否能协同抑制血管损伤后的内膜增殖。我们将在动物模型上测试新的药物组合，观察对雷帕霉素的抗增殖作用的耐药性。

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.