Misguided angiogenesis, plexiform pulmonary hypertension

误导性血管生成、丛状肺动脉高压

• 批准号: 6642927
• 负责人: NORBERT F VOELKEL
• 金额: $ 21.34万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6642927
• 关键词: angiogenesis; athymic mouse; cell growth regulation; cell population study; cell proliferation; disease /disorder etiology; gene expression; gene mutation; growth factor receptors; human subject; human tissue; microarray technology; molecular pathology; patient oriented research; pulmonary hypertension; tissue /cell culture; transforming growth factors; vascular endothelial growth factors; vascular endothelium

DESCRIPTION (provided by applicant): Primary pulmonary hypertension (PPH) is a devastating disease that occurs in a familial and a sporadic form, sometimes associated with AIDS, anorexigen drug intake and with chronic liver disease. We have found that PPH is categorically different from plexogenic secondary pulmonary hypertension (2nd PH) in that the proliferative endothelial cells in PPH are monoclonal, whereas they are strictly polyclonal in secondary PH. We postulate that the exuberant endothelial cell proliferation in severe pulmonary hypertension occurs - at least in part -because of mutations of endothelial cell genes involved in apoptosis and growth control. We further postulate that the pathogenesis of PPH can be understood by investigating the concept of misguided vasculogenesis/angiogenesis. Our approach will be to compare pulmonary vascular lesions from patients with PPH that are monoclonal with those from patients that are polyclonal and analyze (using the microarray gene chip technology), the expression pattern in these and in normal lung tissue. The DNA obtained from pulmonary hypertensive vascular lesions will be extracted and subjected to mutational analysis. The focus of the mutational analysis will be on genes associated with endothelial cell growth and apoptosis control. In order to assess the functional importance of VEGF in the development of endothelial cell proliferation and formation of obliterative lesions in PPH lungs we plan to examine to what degree ECV cells that proliferate under high shear stress conditions express an angiogenesis gene pattern. We postulate that endothelial cells which carry a mutation of the TGF-B II gene have a growth advantage and that they will seed at sites of pulmonary arterial bifurcations after they have been injected into the tail vein of nude mice. We will grow circulating endothelial cells from patients with PPH and 2nd PH in culture and examine whether they seed the lung circulation of nude mice and form obliterating lesions.

描述（由申请人提供）： 原发性肺动脉高压（PPH）是一种毁灭性疾病，发生在家族性中 以及一种零星的形式，有时与艾滋病，厌食症药物摄入和 患有慢性肝病。我们发现PPH与 丛生的继发性肺动脉高压（第二pH）是增殖性的 PPH中的内皮细胞是单克隆的，而它们是严格的多克隆 在次要pH中。我们假设旺盛的内皮细胞 严重肺动脉高压的增殖发生 - 至少部分是因为 涉及凋亡和凋亡的内皮细胞基因突变 增长控制。我们进一步假设PPH的发病机理可以是 通过研究误导的概念来理解 血管生成/血管生成。我们的方法是比较肺部 来自PPH患者的血管病变与来自单克隆的患者 多克隆和分析的患者（使用微阵列基因芯片 技术），这些表达模式和正常的肺组织中。这 将提取从肺高血压血管病变获得的DNA 并进行突变分析。突变分析的重点 将与内皮细胞生长和凋亡相关的基因上 控制。为了评估VEGF在 内皮细胞增殖的发展和闭塞形成 PPH肺的病变我们计划检查到哪个程度的ECV细胞 在高剪切应力条件下增殖表达血管生成基因 图案。我们假设携带突变的内皮细胞 TGF-B II基因具有增长优势，它们会在 肺动脉分叉被注入尾巴 裸鼠的静脉。我们将从患者中种植循环的内皮细胞 在培养中使用PPH和第二个pH，检查它们是否播种肺 裸鼠的循环并形成闭塞病变。