Biomarkers of Pulmonary Complications of Scleroderma: The SSc-PAH and

肺动脉高压（PH）发生在10-50%的硬皮病（SSc）患者中，这取决于研究和诊断模式。PH值随着病程的延长而增加，发病年龄越晚，男性和有限SSc患者的PH值越高。PH是SSc患者死亡的主要原因;由于SSc患者的寿命延长，发病率可能会增加。与间质性肺低氧血症导致的PH不同， 在肺动脉高压（PAH）的病理类型中，肺动脉高压主要与局限性SSc（IsSSc）相关，在组织学上与其他形式的肺动脉高压（PAH）相同。SSc-PAH是否与其他形式的PAH具有相似的倾向性和/或分子基础是否相似尚不清楚。与其他形式的PAH相比，除了HIV相关PAH之外，SSc-PAH的特征是自身免疫。我们已经开发的数据表明，在SSC-PAH患者中存在反映免疫过程的分子谱。到 进一步研究以下假设：1）SSc-PAH中的血管变化由EC功能障碍引起，由自身免疫和损伤的相互作用引发，导致随后的过度血管生成; 2）自身免疫和EC损伤和/或血管生成的特异性标志物可以定义SSc人群的表型并预测PAH的发生和进展，我们建议：1）识别炎症/损伤的标志物 和血管生成在患有PAH的SSc患者（SSc-PAH表型）、已确诊的SSc-PAH患者和在本提案有效期内发展为PAH的SSc患者中。2)比较SSc-PAH患者中确定的标志物与SSc-ILD患者中确定的标志物。与Lafyatis博士重叠。 我们将比较和对比“SSc-PAH表型”与“SSc-ILD表型”的候选分子，这两种表型与SSc的发病率和死亡率最相关。3)确定SSc-PAH患者的结局与血管内皮内质网（ER）应激之间的关系。与Trojanowska博士重叠瞄准。拟议的研究将确定一个预测表型 对SSc患者PAH的发生和结局具有重要意义。这可能有助于更好地筛查，识别高危患者，并可能有助于预防策略。

Pulmonary hypertension (PH) occurs in 10-50% of scleroderma (SSc) patients depending on the study and mode of diagnosis. PH increases with disease duration, with later age of disease onset, and is greater in males and in patients with limited SSc. PH is a leading cause of mortality in SSc patients; incidence may be increasing due to longer life span of SSc patients. Unlike PH resulting from hypoxemia due to interstitial lung disease (ILD), PH associated predominantly with limited SSc (IsSSc) is histologically identical to other forms of pulmonary arterial hypertension (PAH). Whether SSc-PAH has similar predispositions to other forms of PAH and/or whether the molecular basis is similar is not known. In contrast to other forms of PAH, with possible exception of HIV-associated PAH, SSc-PAH is characterized by autoimmunity. We have developed data demonstrating that a molecular profile reflecting immune processes exists in patients with SSC-PAH. TO investigate further the hypotheses that: 1) vascular changes in SSc-PAH result from EC dysfunction, initiated by interaction of autoimmunity and injury leading to subsequent excessive angiogenesis; and 2) specific markers of autoimmunity and EC injury and/or angiogenesis can define phenotypes in the SSc population and predict development and progression of PAH, we propose to: 1) Identify markers of inflammation/injury and angiogenesis in SSc patients with PAH (SSc-PAH phenotype) in patients with established SSc-PAH and in SSc patients who develop PAH during the tenure of this proposal. 2) Compare markers identified in patients with SSc-PAH with those markers identified in patients with SSc-ILD. Overlap Aim with Dr. Lafyatis. We will compare and contrast candidate molecules of the "SSc-PAH phenotype" with those of the "SSc-ILD phenotype", the two phenotypes most associated with morbidity and mortality in SSc. 3) Determine the relationship between outcomes in patients with SSc-PAH and vascular endothelial endoplasmic reticulum (ER) stress. Overlap Aim with Dr. Trojanowska. The proposed studies will determine a predictive phenotype important in development and outcome of PAH in SSc patients. This may allow better screening, identify atrisk patients and, potentially, contribute to prevention strategies.