Pathobiology of Severe Pulmonary Hypertension

严重肺动脉高压的病理学

• 批准号: 6642859
• 负责人: NORBERT F VOELKEL
• 金额: $ 110.26万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-17 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6642859
• 关键词: pulmonary hypertension

DESCRIPTION (provided by applicant): This PPG application has evolved from three presently active R01 grants, which this application intends to replace. Severe chronic pulmonary hypertension (PH) - in spite of intravenous prostacyclin (PGI2) treatment - remains an important and challenging clinical problem. Our four projects have been designed to investigate specific aspects of human PH including primary and neonatal pulmonary hypertension. We start with the concept that pulmonary arteries differ from systemic vessels in that their response to "stress" or "injury" is different. We further postulate that the adult lung circulation remodels with endothelial cell proliferation (Project 1), whereas the neonatal lung circulation remodels without endothelial cell proliferation (Project 2). Vascular endothelial growth factor (VEGF) and its receptor, KDR. are critically involved in the formation of plexiform lesions in adult PH whereas reduced VEGF/KDR signaling in the fetus leads to a vasculogenesis failure characterized by a muscularized, pruned vascular tree. Project 3 develops a prospectively designed new rodent model of endothelial cell-proliferative, severe PH that has been built on inhibition of the VEGF receptor KDP, and proposes that endothelial cell death selects for the emergence of resistant, proliferative endothelial cells at sites of high shear stress. We anticipate that this rat model will permit the systematic investigation of the interplay between altered vasoreactivity (vasoconstriction) and development of obliterative pulmonary vascular arteriopathy. The information gathered from this model will include lung tissue transcript information gathered using the microarray GeneChip technology and will be compared with the gene expression data obtained from human PPH and 2nd PH lungs (Project 1). The fact that endothelial cell proliferation in PPH is monoclonal encourages the search for gene mutations. One candidate mutated gene is the TGF-B-RII gene coding for the TGF-B-II receptor, which is involved in cell growth/death control. Lastly, a severe loss of prostacyclin receptor (PGII-R) expression in the resistance vessels of PPH lungs provides rationale and focus for the investigation of the role of PGI2 and its receptor in pulmonary vascular remodeling (Project 4). Vascular smooth muscle cells from genetically engineered mice (Lung-specific PGI2-synthase gene overexpression and PGI2-receptor knock-out) will be examined for PGI2-R-dependent and independent growth. We believe that this highly integrated program addresses central issues of the pathobiology of severe human pulmonary hypertension.

描述（由申请人提供）： 该 PPG 应用程序是从目前活跃的三项 R01 拨款发展而来的，其中 此应用程序旨在替换。严重慢性肺动脉高压 (PH) - 尽管静脉注射前列环素 (PGI2) 治疗 - 仍然是一种 重要且具有挑战性的临床问题。我们的四个项目已 旨在研究人类PH值的特定方面，包括原发性和 新生儿肺动脉高压。我们从肺的概念开始 动脉与全身血管的不同之处在于它们对“压力”或 “伤”则不同。我们进一步假设成人肺循环 随着内皮细胞增殖进行重塑（项目 1），而新生儿 肺循环重塑而无内皮细胞增殖（项目 2）。 血管内皮生长因子 (VEGF) 及其受体 KDR。是 严重参与成人 PH 丛状病变的形成，而 胎儿中 VEGF/KDR 信号传导减少导致血管生成失败 其特征是肌肉化、修剪过的维管树。项目3开发 前瞻性设计的新的内皮细胞增殖啮齿动物模型， 严重的 PH 是建立在抑制 VEGF 受体 KDP 的基础上的，以及 提出内皮细胞死亡选择了耐药性的出现， 高剪切应力部位的增殖内皮细胞。我们预计 该大鼠模型将允许系统地研究相互作用 血管反应性改变（血管收缩）和发展之间 闭塞性肺血管病。收集的信息来自 该模型将包括使用收集的肺组织转录信息 微阵列基因芯片技术并将其与基因表达进行比较 从人类 PPH 和第二 PH 肺获得的数据（项目 1）。事实是 PPH 中的内皮细胞增殖是单克隆的，鼓励寻找 基因突变。一种候选突变基因是 TGF-B-RII 基因，编码 TGF-B-II 受体，参与细胞生长/死亡控制。最后， 耐药中前列环素受体（PGII-R）表达严重丧失 PPH 肺血管为研究提供了理论依据和重点 PGI2 及其受体在肺血管重塑中的作用（项目 4）。 来自基因工程小鼠的血管平滑肌细胞（肺特异性 PGI2 合酶基因过度表达和 PGI2 受体敲除）将 检查 PGI2-R 依赖性和独立生长。我们相信，这 高度综合的计划解决了病理学的核心问题 严重的人类肺动脉高压。