Misguided angiogenesis, plexiform pulmonary hypertension

描述(由申请人提供)： 原发性肺动脉高压(PPH)是一种发生在家族中的破坏性疾病。 以及一种零星的形式，有时与艾滋病、厌食症和吸食药物有关 患有慢性肝病。我们发现，PPH与 增生性增生性肺高压(2PH) PPH中的内皮细胞是单克隆性的，而它们是严格的多克隆性的。 继发性PH。我们推测旺盛的内皮细胞 严重的肺动脉高压会出现增殖--至少部分是因为 参与细胞凋亡的内皮细胞基因的突变和 增长控制。我们进一步假设PPH的发病机制可能是 通过调查误入歧途的概念理解 血管生成/血管生成。我们的方法将是比较肺 PPH患者的血管病变与PPH患者的血管病变是单克隆的 多克隆的患者和分析(使用微阵列基因芯片 技术)，在这些组织和在正常肺组织中的表达模式。这个 从肺动脉高压血管病变中提取的DNA将被提取 并进行突变分析。突变分析的重点 将研究与内皮细胞生长和凋亡相关的基因 控制力。为了评估血管内皮细胞生长因子在血管内皮细胞中的功能重要性 血管内皮细胞增殖与闭塞症的形成 PPH肺的损害我们计划检查ECV细胞在多大程度上 在高剪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血管内皮细胞 转化生长因子-βII基因具有生长优势，它们将在 尾部注射后的肺动脉分叉 裸鼠的静脉。我们将培养患者的循环内皮细胞 用PPH和2PH进行培养，并检查它们是否在肺中种植 裸鼠的血液循环，并形成消融性损伤。

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.