Molecular Determinants of Pulmonary Arterial Hypertension

描述(由申请人提供)： SCCOR的应用重点是了解复杂的肺血管(PV)和右室(RV)重构，导致RV-PV解偶联，以及它们对肺动脉高压(PAH)发病率和死亡率的关键影响。在此应用中，我们将使用硬皮病相关PAH(PAH-SSC)作为临床范例，将其与特发性PAH(IPAH)进行对比，因为其特定的严重性，对现有的PAH治疗缺乏反应，以及潜在的潜在遗传因素决定结果。由于我们广泛的PAH-SSC人群，以及我们在分子和诊断肺部医学和心脏病学方面的专业知识，我们拥有独特的机会，不仅可以更敏感和更清晰地表征PAH-SSC中的RV-PV反应，而且还可以利用最先进的成像、基因组和蛋白质组技术识别潜在治疗的新分子靶点。依靠新的成像系统和分子工具，我们建议对PAHSSc患者进行严格的表型鉴定。有针对性的动物模型将为我们提供更多的候选基因和蛋白质，用于人类研究的特征和靶向。然后，我们将使用功能基因组学和蛋白质组学方法，通过表征潜在的重要多态，验证这些基因在大量表型良好的PAH患者中的临床重要性。这些数据将为PAH-SSC患者的合理治疗提供新的分子基础，并阐明RV-PV功能障碍与遗传易感患者病理基因表达激活的关系。霍普金斯SCCOR应用代表了一个具有多学科专业知识的研究人员联盟，共同的目标是利用最先进的生理、分子、基因组和蛋白质组方法以及新的表型仪器，提供对迄今为止RV-PV功能障碍和解偶联的关键病理生物学过程的最深入了解，并确定与PAH-SSC相关的关键遗传决定因素。在六个高度互动的核心(行政、数据管理/生物信息学、分子病理学、基因组和基因分型、蛋白质组学和成像)的支持下，这五个人类和动物项目将利用新的表型仪器和最先进的分子方法来进行PAH-SSC。我们预计，我们的工作将为有意义的转化性研究提供基础，这些研究将促进新策略的开发，发现治疗靶点，并定义新的生物标记物和预后指标，以限制目前硬皮病相关PAH的悲惨结局。(摘要结束) 个别项目和核心单位 项目1：硬皮病相关的多环芳烃(Hassoun，Paul) 描述(由申请人提供)： 肺动脉高压(PAH)是一种毁灭性的综合征，特别是对于系统性硬化症(SSC)患者，几乎一致地通过右心室(RV)衰竭导致死亡。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，是治疗反应不同的原因，与特发性PAH(IPAH)相比，SSc相关性PAH(PAH-SSC)的结果总体更差。对于可能预测PAH-SSC患者的PAH发展、RV-PV功能障碍、治疗反应和生存的遗传和表型特征，我们知之甚少。SCCOR项目的目的是(I)开发可靠的RV-PV功能测量方法，(Ii)确定SSC中与PAH易感性相关的基因表达模式和候选基因多态，以及(Iii)使用这些工具来指导针对PAH-SSC中RV-PV功能障碍的治疗。在特定的目标#1中，我们将通过血流动力学、超声心动图和磁共振成像来表征表型良好的PAH-SSC患者中RV-PV功能的最佳测量方法，这将补充项目#2中RV-PV解偶联的具体测量。在特定的目标#2中，我们将使用高通量基因组技术来检测基因表达模式，这解释了本项目和项目3中的部分SSC患者对PAH的易感性。分析每种临床条件下的表达模式将使我们能够确定调节一致和不协调的基因簇，将这些基因簇与在特定目标1中开发的功能测量相联系。并确定与PAH-SSC相关的修饰基因图谱。从这些表达研究和项目4和5中的那些，我们将优先考虑新的PAH候选基因。具体目标#3将测试选定疗法对PAH-SSC患者和AIMS#1和#2中确定的其他生物标记物的RV-PV功能的影响。在特定目标#4中，我们将通过对从PAH-SSC患者(目标1)、无PAH的SSC患者(项目3)、IPAH和健康对照的大群体(N=1,000)获得的DNA进行中高通量基因分型，建立优先的PAH候选基因的生物学验证。我们将测试候选基因中选择的变异/单倍型与该组和一个复制的非裔美国人组中PAH的易感性之间的关联。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。(摘要结束)

DESCRIPTION (provided by applicant): This SCCOR application is focused on understanding the complex pulmonary vascular (PV) and right ventricular (RV) remodeling, resulting RV-PV uncoupling, and their crucial impact on morbidity and mortality in Pulmonary Arterial Hypertension (PAH). We will use scleroderma-associated PAH (PAH-SSc) as a clinical paradigm in this application, contrasting it to idiopathic PAH (IPAH), because of its particular severity, lack of response to available PAH therapy, and potential underlying genetic factors that dictate outcome. Because of our extensive PAH-SSc population and our expertise in molecular and diagnostic pulmonary medicine and cardiology, we have the unique opportunity to not only characterize RV-PV responses in PAH-SSc with increased sensitivity and clarity, but to also identify new molecular targets for potential therapy using state of the art imaging, genomic and proteomic technology. Relying on novel imaging systems and molecular tools, we propose to conduct rigorous phenotypic characterization of PAHSSc patients. Focused animal models will provide us with additional candidate genes and proteins for characterization and targeting in human studies. We will then validate the clinical importance of these genes in a large cohort of well-phenotyped patients with PAH, using functional genomics and proteomic approaches with characterization of potentially important polymorphisms. These data will provide new insights into the molecular basis for rational strategies for PAH-SSc patients, and elucidate the relationship of RV-PV dysfunction to the activation of pathological gene expression in genetically susceptible patients. The Hopkins SCCOR application represents a consortium of investigators with multi-disciplinary expertise, and the common goal to utilize state-of-the-art physiological, molecular, and genomic and proteomic approaches as well as novel phenotyping instrumentation that will provide the deepest understanding of the critical pathobiologic processes of RV-PV dysfunction and uncoupling to date, and define key genetic determinants relevant to PAH-SSc. Supported by six highly interactive cores (Administration, Data Management/Bioinformatics, Molecular Pathology, Genomic and Genotyping, Proteomics, and Imaging), the five human and animal projects will utilize novel phenotyping instrumentation and state of the art molecular approaches to PAH-SSc. We anticipate our work will provide a foundation for meaningful translational research that will facilitate development of new strategies, uncover therapeutic targets, and define new biomarkers and prognostic indicators that will limit the current dismal outcome of scleroderma-associated PAH. (End of Abstract) INDIVIDUAL PROJECTS AND CORE UNITS PROJECT 1: Scleroderma-Associated PAH (Hassoun, Paul) DESCRIPTION (provided by applicant): 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. (End of Abstract)