Pathobiology of Severe Pulmonary Hypertension

描述（由申请人提供）： 该PPG申请是从三个目前活跃的R 01赠款演变而来的， 本申请旨在取代。重度慢性肺动脉高压 (PH)- 尽管静脉注射前列环素（PGI 2）治疗-仍然是一个 具有挑战性的临床问题。我们的四个项目 旨在研究人类PH的特定方面，包括原发性和 新生儿肺动脉高压。我们从肺动脉高压的概念开始 动脉与全身血管的不同之处在于，它们对“压力”或 “伤”是不同的。我们进一步假设成人肺循环 重塑与内皮细胞增殖（项目1），而新生儿 无内皮细胞增殖的肺循环重塑（项目2）。 血管内皮生长因子（VEGF）及其受体KDR。是 关键参与成人PH丛状病变的形成，而 胎儿中VEGF/KDR信号传导减少导致血管发生失败 以肌肉发达、修剪整齐的维管树为特征。项目3开发 一种前瞻性设计的内皮细胞增殖的新啮齿动物模型， 在VEGF受体KDP抑制作用基础上建立的重度PH，和 提出内皮细胞死亡选择了耐药的出现， 在高剪切应力的位点处的增殖内皮细胞。我们预计 这种大鼠模型将允许系统地研究 改变的血管反应性（血管收缩）和 闭塞性肺血管性动脉病从以下来源收集的信息 该模型将包括使用 并将基因芯片技术与基因表达谱进行比较 从人PPH和第二PH肺获得的数据（项目1）。的事实 PPH中的内皮细胞增殖是单克隆的，这鼓励了对 基因突变一个候选突变基因是编码以下的TGF-B-RII基因： TGF-B-II受体，其参与细胞生长/死亡控制。最后， 前列环素受体（PGII-R）表达的严重损失， PPH肺的血管提供了研究的基本原理和重点， PGI 2及其受体在肺血管重构中的作用（项目4）。 来自基因工程小鼠的血管平滑肌细胞（肺特异性 PGI 2-合成酶基因过表达和PGI 2-受体敲除）将被 检查PGI 2-R依赖性和独立性生长。我们认为这 高度集成的方案解决了核心问题的病理生物学 严重的人类肺动脉高压

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.