Peripheral Blood Cells in Severe Pulmonary Hypertention

描述（由申请人提供）： 最近的工作强调了增殖的内皮细胞在肺动脉高压（PAH）发病机制中的重要性。 我们建议在两个互补的方面研究PAH的疾病过程。 首先，我们探索了外周血细胞作为PAH疾病生物标志物的潜在作用。 我们已经成功地证明了PAH患者与正常对照相比循环单核细胞基因表达的显著和预测性改变。 我们还发现这些患者外周血中内皮前体细胞数量增加。 我们对这种疾病的第二种方法集中在负责内皮细胞增殖的机制上。 我们最近报道了特发性肺动脉高压患者肺血管内皮细胞内存在人类疱疹病毒8型（HHV-8）感染的证据。 我们推测HHV-8感染在这种疾病的内皮细胞增殖特征中起着致病作用。 我们现在建议扩大这些重要的初步发现。 首先，我们希望进一步明确外周血细胞基因表达作为肺动脉高压生物标志物的相关性和重要性。其次，我们希望研究HHV-8感染对培养的肺微血管内皮细胞以及对特发性肺动脉高压（IPAH/PPH）患者循环内皮前体细胞的影响。 该项目的具体目标是： 1)使用外周血单核细胞基因微阵列开发区分模型，区分IPAH/PPH患者与硬皮病CREST变异相关的肺动脉高压患者。 2)评价HHV-8感染对PAH患者的人肺微血管内皮细胞、血液生长内皮细胞和内皮前体细胞的细胞生长、细胞凋亡和整体基因表达的影响。

DESCRIPTION (provided by applicant): Recent work has emphasized the importance of proliferating, endothelial cells in the pathogenesis of pulmonary arterial hypertension (PAH). We have proposed studying the disease process of PAH on two complimentary fronts. First, we have explored the potential role of peripheral blood cells as biomarkers of disease in PAH. We have successfully demonstrated significant and predictive alterations in the gene expression of circulating mononuclear cells in patients with PAH compared to normal controls. We have also found increased numbers of endothelial precursor cells within the peripheral blood of these patients. Our second approach to this disease has focused on mechanisms responsible for the endothelial cell proliferation. We have recently reported evidence of human Herpesvirus-8 (HHV-8) infection within the pulmonary vascular endothelial cells of patients with idiopathic pulmonary arterial hypertension. We speculate that HHV-8 infection plays a causative role in the endothelial cell proliferation characteristic of this disease. We now propose to expand upon these important preliminary findings. First, we wish to further define the relevance and importance of peripheral blood cell gene expression as a biomarker of pulmonary arterial hypertension. Second, we wish to investigate the effect of HHV-8 infection on cultured pulmonary microvascular endothelial cells as well as on circulating endothelial precursor cells from patients with idiopathic pulmonary arterial hypertension (IPAH/PPH). The specific aims of this project are: 1) Develop discrimination models using gene microarrays of peripheral blood mononuclear cells which distinguish patients with IPAH/PPH from patients with pulmonary hypertension related to the CREST variant of scleroderma. 2) Evaluate the effect on cell growth, apoptosis and global gene expression of HHV-8 infection in human pulmonary microvascular endothelial cells, blood outgrowth endothelial cells and endothelial precursor cells from patients with PAH.