SCLERODERMA-ASSOCIATED PAH

硬皮病相关的 PAH

• 批准号: 8013836
• 负责人: Paul M. Hassoun
• 金额: $ 58.24万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8013836
• 关键词: Accounting; Address; African American; Alleles; Animal Model; Arts; Biological; Biological Markers; Blood Vessels; Candidate Disease Gene; Cardiopulmonary; Cardiovascular system; Categories; Cessation of life; Characteristics; Clinical; Clinical Research; Code; Complement; DNA; Data; Development; Diagnosis; Disease; Dissection; Failure; Frequencies; Functional disorder; Future; Gene Cluster; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Polymorphism; Genomics; Genotype; Haplotypes; Human; Human Resources; Link; Literature; Lung; Magnetic Resonance Imaging; Measurement; Measures; Mind; Molecular; Molecular Profiling; Nucleic Acid Regulatory Sequences; Outcome; Outcome Measure; Patients; Pattern; Phenotype; Population; Predisposition; Prevalence; Pulmonary Hypertension; Research Design; Research Personnel; Right Ventricular Function; Right-On; Scleroderma; Severities; Syndrome; Systemic Scleroderma; Technology; Testing; Therapeutic; Validation; Variant; Ventricular; Walking; Work; analytical tool; base; cDNA Arrays; cohort; effective therapy; hemodynamics; high risk; improved; instrument; mortality; novel; primary pulmonary hypertension; programs; pulmonary arterial hypertension; response; tool

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.

肺动脉高压（PAH）是一种破坏性综合征，特别是对于患有全身性心脏病的患者 硬化症（SSc），几乎无一例外地因右心室（RV）衰竭而导致死亡。我们假设 涉及肺血管系统 (PV) 和 RV 的结构变化的严重程度，导致 严重的 RV-PV 功能障碍，导致对治疗的不同反应以及总体较差的结果 SSc 相关性 PAH (PAH-SSc) 与特发性 PAH (IPAH) 相比。人们对遗传和基因知之甚少 可能预测 PAH 发生、RV-PV 功能障碍、对药物反应的表型特征 PAH-SSc 患者的治疗和生存。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识别候选基因 与 SSc 中 PAH 易感性相关的基因多态性，以及 (iii) 使用这些工具来指导治疗 针对 PAH-SSc 中的 RV-PV 功能障碍。在具体目标#1中，我们将描述以下最佳措施 RV-PV 功能通过血流动力学、超声心动图和磁共振成像剖面来确定 表型 PAH-SSc 患者，这将补充 RV-PV 解偶联的特定测量 项目#2。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，这解释了 SSc 患者亚群对 PAH 的易感性 项目和项目 3。分析每种临床条件下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 具体目标 #1 中开发的功能测量，并确定相关的修饰基因谱 与 PAH-SSc。从这些表达研究以及项目 4 和 5 中的研究中，我们将优先考虑新型 PAH 候选基因。具体目标 #3 将测试所选疗法对 PAH-SSc 中 RV-PV 功能的影响 目标 #1 和目标 #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 通过对所获得的 DNA 进行中通量和高通量基因分型来验证优先 PAH 候选基因 来自一大群 (N=1,000) 具有广泛特征的 PAH-SSc 患者（目标 #1），SSc 没有 PAH（项目 #3）、IPAH 和健康对照。我们将测试选择之间的关联 该组和重复组中候选基因的变异/单倍型以及 PAH 的易感性 非裔美国人。完成这些研究将提供指导未来的宝贵信息 旨在改善 PAH-SSc 临床结果的机制和临床研究。