Molecular Determinants of Pulmonary Arterial Hypertension

此SCCOR应用程序专注于了解复杂的肺血管(PV)和右 心室(RV)重构、导致的RV-PV解偶联及其对发病率和死亡率的重要影响 在肺动脉高压(PAH)中。我们将使用硬皮病相关多环芳烃(PAH-SSC)作为 这一应用中的临床范例，将其与特发性PAH(Ipah)进行对比，因为其特殊的 严重程度，对可用的PAH治疗缺乏反应，以及潜在的潜在遗传因素 结果。由于我们广泛的PAH-SSC人群以及我们在分子和诊断方面的专业知识 肺部医学和心脏病学，我们有独特的机会不仅可以表征RV-PV 在PAH-SSC中的响应具有更高的灵敏度和清晰度，但也识别新的分子靶点 使用最先进的成像、基因组和蛋白质组技术的潜在治疗。依托小说 成像系统和分子工具，我们建议对PAHSSc进行严格的表型表征 病人。聚焦的动物模型将为我们提供更多的候选基因和蛋白质 人体研究中的特征和目标。然后我们将验证这些基因的临床重要性。 在一大群表型良好的PAH患者中，使用功能基因组学和蛋白质组学 具有潜在重要多态特征的方法。这些数据将提供新的 对PAH-SSC患者合理策略的分子基础的洞察，并阐明两者之间的关系 在遗传易感患者中，RV-PV功能障碍对病理基因表达激活的影响。 霍普金斯SCCOR申请代表了一个拥有多学科专业知识的调查财团， 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，将提供对 到目前为止，RV-PV功能障碍和解偶联的关键病理生物学过程，并定义关键基因 与PAH-SSC相关的决定因素。由六个高度交互的核心(管理、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)、 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 PAH-SSC的途径。我们期待我们的工作将为有意义的翻译提供基础 研究将促进新策略的开发，发现治疗靶点，并定义新的 生物标志物和预后指标将限制硬皮病相关患者目前的悲惨结局 啊哈。

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.