Pathobiology of Severe Pulmonary Hypertension

描述(由申请人提供)： 此PPG应用程序由三个当前有效的R01授权演变而来， 此应用程序打算替换。重度慢性肺动脉高压 (PH)--尽管接受了静脉注射前列环素(PGI2)--仍然是一个 这是一个重要且具有挑战性的临床问题。我们的四个项目是 旨在研究人类PH的特定方面，包括原发和 新生儿肺动脉高压。我们从肺脏的概念开始 动脉与全身血管的不同之处在于它们对“压力”或 “受伤”是不同的。我们进一步假设成人的肺循环 改建内皮细胞增殖(项目1)，而新生儿 无内皮细胞增殖的肺循环重建(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 胎儿中血管内皮生长因子/KDR信号的降低导致血管生成失败 以肌肉发达的、修剪的维管束树为特征的。项目3开发 一种前瞻性设计的新的内皮细胞-增殖性啮齿动物模型 严重的PH，建立在抑制VEGF受体KDP的基础上，以及 认为内皮细胞死亡是耐药细胞产生的原因， 高切应力部位的增殖内皮细胞。我们期待着 这种大鼠模型将允许对相互作用进行系统的研究 血管反应性改变(血管收缩)与 闭塞性肺血管病。从以下地点收集的信息 该模型将包括使用 微阵列基因芯片技术及其与基因表达的比较 来自人类PPH和第二肺PH的数据(项目1)。事实是， 内皮细胞在PPH中的增殖是单克隆性的，鼓励探索 基因突变。一个候选突变基因是编码以下基因的转化生长因子-B-RII 参与细胞生长/死亡控制的转化生长因子-β-II受体。最后， 前列环素受体(PGII-R)在耐药中的表达严重缺失 PPH肺血管为PPH的研究提供了理论基础和重点。 前列环素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合酶基因过表达和PGI2受体敲除)将 检查PGI2-R依赖和独立生长。我们相信这一点 高度集成的计划解决了该病病理生物学的中心问题 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.