SCLERODERMA-ASSOCIATED PAH

肺动脉高压（PAH）是一种毁灭性的综合征，特别是对于全身性肺动脉高压的患者。 硬化症（SSc），几乎一致地导致通过右心室（RV）衰竭而死亡。我们假设 涉及肺血管（PV）和RV的结构变化的严重程度，导致 严重的RV-PV功能障碍，导致对治疗的反应不同， SSc相关PAH（PAH-SSc）与特发性PAH（IPAH）的比较。对基因和 可能预测PAH发生、RV-PV功能障碍、 治疗和PAH-SSc患者的生存率。该SCCOR项目的目标是（i）开发 RV-PV功能的可靠测量，（ii）表征基因表达模式并鉴定候选的 与SSc中PAH易感性相关的基因多态性，以及（iii）使用这些工具指导治疗 旨在治疗PAH-SSc中的RV-PV功能障碍。在具体目标#1中，我们将描述 通过血流动力学、超声心动图和磁共振成像曲线确定RV-PV功能- PAH-SSc表型患者，这将补充RV-PV解偶联的特异性测量， 二号工程。在具体目标#2中，我们将采用高通量基因组技术来检查 基因表达模式，解释了SSc患者亚群对PAH的易感性， 项目和项目3。在每种临床条件下分析的表达模式将使我们能够 确定一致和不一致调节的基因簇，将这些基因簇与 在特定目标#1中开发的功能测量，并确定相关的修饰基因谱 关于PAH-SSc根据这些表达研究以及项目4和5中的研究，我们将优先考虑新型PAH 候选基因具体目标#3将检测选定治疗对PAH-SSc患者RV-PV功能的影响 目标#1和#2中确定的患者和其他生物标志物。在具体目标#4中，我们将建立生物学 通过获得的DNA的中通量和高通量基因分型验证优先PAH候选基因 来自大量（N= 1，000）广泛表征的PAH-SSc患者（目的#1），SSc无 PAH（项目3）、IPAH和健康对照。我们将测试选择的 候选基因的变异/单倍型和PAH的易感性，在该组和重复组中， 非裔美国人这些研究的完成将提供宝贵的信息，指导今后的工作。 旨在改善PAH-SSc临床结局的机制和临床研究。

Pulmonary arterial hypertension (PAH) is a devastating syndrome, particularly for patients with systemic sclerosis (SSc), leading almost uniformly to death through right ventricular (RV) failure. We hypothesize that the severity of structural changes involving the pulmonary vasculature (PV) and the RV, resulting in severe RV-PV dysfunction, accounts for diverging responses to therapy and an overall worse outcome in SSc-related PAH (PAH-SSc) as compared to idiopathic PAH (IPAH). Little is known about genetic and phenotypic characteristics that might predict the development of PAH, RV-PV dysfunction, response to therapy, and survival in patients with PAH-SSc. The objectives of this SCCOR project are to (i) develop reliable measures of RV-PV function, (ii) characterize patterns of gene expression and identify candidate gene polymorphisms associated with susceptibility to PAH in SSc, and (iii) use these tools to guide therapy aimed at RV-PV dysfunction in PAH-SSc. In Specific Aim #1, we will characterize optimal measures of RV-PV function by hemodynamic, echo-cardiographic, and Magnetic Resonance Imaging profiles in well- phenotyped patients with PAH-SSc, which will complement specific measurements of RV-PV uncoupling in Project #2. In Specific Aim #2, we will employ high throughput genomic technologies to examine the patterns of gene expression, which explain susceptibility to PAH in subsets of patients with SSc from this project and Project 3. Patterns of expression analyzed within each clinical condition will allow us to determine both concordantly and discordantly regulated gene clusters, link these gene clusters with functional measurements developed in Specific Aim #1, and determine modifier gene profiles associated with PAH-SSc. From these expression studies and those in Projects 4 and 5 we will prioritize novel PAH candidate genes. Specific Aim #3 will test the effects of selected therapies on RV-PV function in PAH-SSc patients and other biomarkers identified in Aims #1 and #2. In Specific Aim #4, we will establish biological validation of prioritized PAH candidate genes via mid- and high-throughput genotyping of DNA procured from a large group (N=1,000) of extensively characterized patients with PAH-SSc (Aim #1), SSc without PAH (Project #3), IPAH, and healthy controls. We will test for association between select variants/haplotypes in candidate genes and susceptibility of PAH in this group and a replicate group of African-Americans. Completion of these studies will provide invaluable information that will guide future mechanistic and clinical studies designed to improve clinical outcomes in PAH-SSc.