EFFECTS OF STATINS ON PULMONARY HYPERTENSION

描述(由申请人提供)： 这一指导临床科学家发展奖的候选人对肺动脉高压疾病具有强烈的临床兴趣，并致力于该领域的研究事业。该候选人所在的机构在培养杰出的临床和基础科学家方面有着悠久而丰富的历史，并为学术生涯发展提供了无与伦比的环境。发起人和联合发起人是国际知名的肺动脉高压(PH)病理生物学专家。咨询委员会的第三位成员是肺内皮细胞生物学和小G蛋白信号方面的专家。候选人将接受严密监督的研究培训，以及精心挑选的教学指导计划。该研究计划将检验3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂(他汀类)缓解肺动脉高压的假设。内皮功能障碍是重度PH血管过度收缩和血管壁细胞异常增殖的关键因素。他汀类药物已被证明可以通过抑制小G蛋白的预烯基化来改善几种正常的内皮细胞功能，而不是通过降低胆固醇的作用。候选人已经获得了初步数据，表明他汀类药物可以减轻大鼠的慢性缺氧性PH。具体目的#1将测试他汀类药物在慢性低氧加血管内皮生长因子受体-2阻断诱导的重度PH大鼠模型中减轻PH和肺血管重构的能力。该模型具有明显的内皮细胞和平滑肌细胞增殖的特点，与人的肺动脉高压非常相似。具体目标#2将在该模型中探索他汀类药物治疗有益效果的细胞和分子机制。这项研究的长期目标是：1)探索他汀类药物作用的细胞转导机制，2)基于这些概念在人类PH患者中进行翻译研究，最终，3)开发这种威胁生命的疾病的新疗法。这一奖项将允许候选人发展成为一名训练有素的PH独立研究员。

DESCRIPTION (provided by applicant): The candidate for this mentored clinical scientist development award has a strong clinical interest in pulmonary hypertensive disorders and is committed to a research career in this field. The candidate's institution has a long, rich history of training distinguished clinical and basic scientists and provides an unparalleled environment for academic career development. The sponsor and co-sponsor are internationally acclaimed experts in the pathobiology of pulmonary hypertension (PH). The third member of the Advisory Committee is an expert in pulmonary endothelial cell biology and small G-protein signaling. The candidate will receive closely supervised research training, as well as a carefully selected program of didactic instruction. The research plan will test the hypothesis that 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) attenuate pulmonary hypertension. Endothelial dysfunction is a key factor in the excessive vasoconstriction and abnormal vascular wall cell proliferation of severe PH. Statins have been shown to improve several normal endothelial cell functions, independent of their cholesterol lowering effect, through inhibition of small G-protein prenylation. The candidate has obtained preliminary data demonstrating that statins attenuate chronic hypoxic PH in rats. Specific aim #1 will test the ability of statins to attenuate PH and pulmonary vascular remodeling in a rat model of severe PH induced by chronic hypoxia plus vascular endothelial growth factor receptor-2 blockade. This model is characterized prominent endothelial as well smooth muscle cell proliferation, closely resembling human pulmonary arterial hypertension. Specific aim #2 will explore the cellular and molecular mechanisms responsible for the beneficial effect of statin treatment in this model. The long-term objectives of this research are to: 1) probe the cellular transduction mechanisms involved in the effects of statins, 2) to perform translational studies in humans with PH based on these concepts and ultimately, 3) to develop novel therapies for this life-threatening disorder. This award will allow the candidate to develop into a well-trained independent researcher in PH.