HYPERTENSIVE PULMONARY VASCULAR REMODELING--ROLE OF IGF

研究：提出的研究探索了血管形成的机制 慢性高血压性肺动脉重塑。肺 高血压是一种严重的疾病，与显著的发病率有关。 和死亡率。血管相关性慢性肺动脉高压 重塑的特点是对氧气治疗反应有限。 和血管扩张剂。对重塑过程的更好理解将 希望能带来治疗干预。这项建议审查了 多肽生长因子在细胞增殖/肥大中的作用 细胞外基质(ECM)产生增加的特点 高血压肺血管重塑。研究最初将集中在 对胰岛素样生长因子I(IGF-I)的影响，并在以后研究可能 血小板衍生生长因子与转化的协同作用 生长因子-β(TGF-β)。建议的大多数实验将是 体外分离的大鼠肺动脉细胞 新生牛犊，通常在模拟导致他死亡的条件下 慢性肺动脉高压的体内发展(低氧，模拟 血流动力学应力)。将作出相当大的努力将这些联系起来 新生小牛重度慢性低氧模型的体外研究 在本实验室发生了肺动脉高压。具体目标将是 致： 1)研究IGF-I对正常新生牛PA平滑的影响 肌细胞(SMC)和成纤维细胞与细胞增殖 和ECM生产， 2)确定IGF-I的产生和/或反应性是否通过血管壁 细胞在与发育相关的条件下增加 慢性缺氧性肺动脉高压， 3)研究血小板衍生生长因子和转化生长因子-β与胰岛素样生长因子-I的协同作用。 细胞增殖和细胞外基质的产生 低氧和模拟血流动力学应激。 环境：肺动脉高压的发病机制正在深入研究中 医院心肺研究实验室的调查 科罗拉多大学丹佛分校。这是一个大型实验室，有许多 非常合格的临床科学家，一流的设备，设施， 和技术支持，以及为研究人员做准备的声誉 作为独立调查员的成功职业生涯。在学术上很大的- 科罗拉多大学定向肺科进一步加强 职业发展的环境。

Research: The research proposed explores the mechanisms of vascular remodeling in chronically hypertensive pulmonary arteries (PA). Pulmonary hypertension is a serious disorder associated with significant morbidity and mortality. Chronic pulmonary hypertension associated with vascular remodeling is characterized by limited response to treatment with oxygen and vasodilators. Improved understanding of the remodeling process would hopefully lead to therapeutic interventions. This proposal examine the role of peptide growth factors in the cellular hyperplasia/hypertrophy and increased extracellular matrix (ECM) production characteristic of hypertensive pulmonary vascular remodeling. Studies will initially focus on insulin-like growth factor I (IGF-I), and later examine possible synergism with platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF-B). Most of the experiments proposed will be carried out in vitro on cells isolated from the pulmonary arteries of neonatal calves, often under conditions simulating those which lead tot he development of chronic pulmonary hypertension in vivo (hypoxia, simulated hemodynamic stress). Considerable effort will be made to relate these in vitro studies to the neonatal calf model of severe chronic hypoxic pulmonary hypertension developed in this laboratory. Specific Aims will be to: 1) Characterize the effects of IGF-I on normal neonatal bovine PA smooth muscle cells (SMC) and fibroblasts with regard to cellular proliferation and ECM production, 2) Determine if IGF-I production and/or responsiveness by vascular wall cells are increased under conditions associated with the development of chronic hypoxic pulmonary hypertension, 3) Study possible synergism of PDGF and TGF-B with IGF-I with regard to cellular proliferation and ECM production, in the presence and absence of hypoxia and simulated hemodynamic stress. Environment: The pathogenesis of pulmonary hypertension is under intensive investigation in the Cardiovascular Pulmonary Research Laboratory at the University of Colorado in Denver. This is a large laboratory with many very well qualified clinical scientists, excellent equipment, facilities, and technical support, and a reputation for preparing researchers for successful careers as independent investigators. The large academically- oriented Pulmonary Division at the University of Colorado further enhances the environment for career development.