Molecular Determinants of Pulmonary Arterial Hypertension

描述（由申请人提供）： 该SCCOR应用程序的重点是了解复杂的肺血管（PV）和右心室（RV）重塑，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。我们将使用硬皮病相关PAH（PAH-SSc）作为本申请的临床范例，将其与特发性PAH（IPAH）进行对比，因为其特殊的严重程度、对现有PAH治疗缺乏反应以及决定结局的潜在潜在遗传因素。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，我们不仅有独特的机会以更高的灵敏度和清晰度表征PAH-SSc中的RV-PV反应，而且还可以使用最先进的成像，基因组学和蛋白质组学技术确定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表征。重点动物模型将为我们提供更多的候选基因和蛋白质，用于人类研究的表征和靶向。然后，我们将使用功能基因组学和蛋白质组学方法，通过表征潜在重要的多态性，在一个大型的PAH表型良好的患者队列中验证这些基因的临床重要性。这些数据将为PAH-SSc患者的合理策略提供新的分子基础，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申请代表了一个具有多学科专业知识的研究者联盟，共同目标是利用最先进的生理学、分子学、基因组学和蛋白质组学方法以及新型表型分析仪器，最深入地了解迄今为止RV-PV功能障碍和解偶联的关键病理生物学过程，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（管理，数据管理/生物信息学，分子病理学，基因组学和基因分型，蛋白质组学和成像）的支持下，五个人类和动物项目将利用新的表型分析仪器和最先进的分子方法来PAH-SSc。我们预计我们的工作将为有意义的转化研究提供基础，这将促进新策略的开发，发现治疗靶点，并定义新的生物标志物和预后指标，这将限制硬皮病相关PAH目前令人沮丧的结局。(End摘要） 个别项目和核心单位 项目1：硬皮病相关PAH（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，与特发性PAH（IPAH）相比，涉及肺血管（PV）和RV的结构变化的严重程度导致重度RV-PV功能障碍，导致对治疗的反应不同，并且SSc相关PAH（PAH-SSc）的总体结局更差。关于可能预测PAH-SSc患者PAH发展、RV-PV功能障碍、治疗反应和生存率的遗传和表型特征知之甚少。该SCCOR项目的目的是（i）开发可靠的RV-PV功能测量方法，（ii）表征基因表达模式并确定与SSc中PAH易感性相关的候选基因多态性，以及（iii）使用这些工具指导针对PAH-SSc中RV-PV功能障碍的治疗。在特定目标1中，我们将通过血流动力学、超声心动图和磁共振成像特征来表征具有良好表型的PAH-SSc患者的RV-PV功能的最佳测量值，这将补充项目2中RV-PV解偶联的特定测量值。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，这解释了本项目和项目3中SSc患者亚组对PAH的易感性。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相关的修饰基因谱。根据这些表达研究以及项目4和5中的研究，我们将优先考虑新的PAH候选基因。具体目标3将检测选定治疗对PAH-SSc患者RV-PV功能的影响以及目标1和目标2中确定的其他生物标志物。在具体目标#4中，我们将通过对从大量（N = 1，000）广泛表征的PAH-SSc（目标#1）、无PAH的SSc（项目#3）、IPAH和健康对照患者中获得的DNA进行中通量和高通量基因分型，建立优先PAH候选基因的生物学验证。我们将测试候选基因中的选择变体/单倍型与该组和重复的非裔美国人中PAH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临床结局的机制和临床研究。(End摘要）

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)