HYPERTENSIVE PULMONARY VASCULAR REMODELING--ROLE OF IGF

研究：这项研究探索了血管紧张素转换酶的机制。 慢性高血压肺动脉（PA）重塑。 肺 高血压是一种严重的疾病， and mortality. 慢性肺动脉高压与血管性 重塑的特征在于对氧治疗的有限反应 和血管扩张剂。 对重塑过程的更好理解将 希望能导致治疗干预。 这项建议审查了 肽生长因子在细胞增生/肥大中的作用， 细胞外基质（ECM）产生增加是 高血压肺血管重构 研究将首先关注 胰岛素样生长因子I（IGF-I），并随后检查可能的 协同血小板衍生生长因子（PDGF）和转化 生长因子β（TGF-β）。 大多数实验都是 在体外对从肺动脉分离的细胞进行， 新生小牛，通常在模拟那些导致他死亡的条件下， 体内慢性肺动脉高压的发展（缺氧，模拟 血液动力学应力）。 将作出相当大的努力， 新生犊牛严重慢性缺氧模型的体外研究 肺动脉高压的症状 具体目标将是 收件人： 1)IGF-I对正常新生牛PA平滑肌的影响 肌细胞（SMC）和成纤维细胞的细胞增殖 和ECM生产， 2)确定血管壁是否产生IGF-I和/或反应性 细胞在与发展相关的条件下增加， 慢性低氧性肺动脉高压， 3)研究PDGF和TGF-B与IGF-I在以下方面的可能协同作用： 细胞增殖和ECM产生，在存在和不存在 缺氧和模拟血流动力学应激。 环境：肺动脉高压的发病机制尚不十分清楚 心血管肺研究实验室的研究 丹佛的科罗拉多大学。 这是一个大型实验室， 非常合格的临床科学家，一流的设备，设施， 和技术支持，以及为研究人员准备的声誉， 作为独立调查员的成功职业。 学术上的大- 科罗拉多大学面向肺科进一步提高 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.