SCLERODERMA-ASSOCIATED PAH

肺动脉高压(PAH)是一种毁灭性的综合征，尤其是对系统性心脏病患者。 硬化症(SSC)，通过右室(RV)衰竭几乎一致地导致死亡。我们假设 涉及肺血管系统(PV)和RV的结构变化的严重性，导致 严重的RV-PV功能障碍，是治疗反应不同和总体预后更差的原因 SSC相关PAH(PAH-SSC)与特发性PAH(IPAH)的比较。对基因和基因的了解很少 可能预测PAH、RV-PV功能障碍的表型特征，对 PAH-SSC患者的治疗和存活率。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确定候选基因 SSC中与PAH易感性相关的基因多态，以及(Iii)使用这些工具指导治疗 针对PAH-SSC的RV-PV功能障碍。在具体目标#1中，我们将描述下列最佳度量 应用血流动力学、超声心动图和磁共振成像研究井下RV-PV功能 PAH-SSC表型患者，这将补充RV-PV解偶联的具体测量 项目#2。在特定目标#2中，我们将使用高通量基因组技术来检查 基因表达模式，这解释了由此产生的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 确定一致性和非一致性调节的基因簇，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图谱 用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多环芳烃 候选基因。特定目标#3将测试选定疗法对PAH-SSC患者RV-PV功能的影响 在目标1和目标2中确定的患者和其他生物标记物。在具体目标4中，我们将建立生物 通过获得的DNA的中高通量基因分型验证优先的多环芳烃候选基因 来自一大群具有广泛特征的PAH-SSC患者(N=1,000)(目标1)，SSC没有 PAH(项目3)、IPAH和健康对照。我们将测试SELECT之间的关联 候选基因的变异/单倍型与PAH在本组和复制组中的易感性 非裔美国人。这些研究的完成将提供宝贵的信息，指导未来 旨在改善PAH-SSC临床结果的机制和临床研究。

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.