Molecular Determinants of Pulmonary Arterial Hypertension

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。

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.