A molecular phenotype of combined pulmonary hypertension

合并性肺动脉高压的分子表型

• 批准号: 9324353
• 负责人: Anna R Hemnes
• 金额: $ 30.49万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-17 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9324353
• 关键词: Affect; Animal Model; Blood; Blood Vessels; CAV1 gene; Classification; Clinical Data; Clinical Research; Complex; Confusion; Coupled; DNA Databases; Data; Descriptor; Development; Discriminant Analysis; Discrimination; Disease; Enrollment; Epidemiology; Evaluation; Frequencies; Functional disorder; General Population; Genetic; Genetic Predisposition to Disease; Genetic Transcription; Genomics; Goals; Heart Atrium; Heart Diseases; Heritability; High Prevalence; Hypertension; Insulin Resistance; International; Knowledge; Lead; Left; Link; Liquid substance; Lung; Lung diseases; Magnetic Resonance Imaging; Measures; Medical; Metabolic; Metabolic syndrome; Methodology; Molecular; Mutation; Myocardial dysfunction; Nitric Oxide; Ontology; Pathologic; Pathology; Patients; Phenotype; Physiological; Physiology; Protocols documentation; Publishing; Pulmonary Hypertension; Pulmonary Wedge Pressure; Pulmonary artery structure; Recommendation; Reporting; Research Infrastructure; System; Techniques; Testing; Time; Uncertainty; Vascular Diseases; Vascular remodeling; Ventricular; Work; arterial remodeling; biobank; bone morphogenic protein; clinical phenotype; cost; endophenotype; exome sequencing; genetic variant; hemodynamics; improved; medical specialties; metabolomics; molecular phenotype; outcome forecast; peripheral blood; pressure; pulmonary arterial hypertension; response; symposium; targeted treatment; tool; trait; transcriptome; transcriptomics; treatment response; vasoconstriction

DESCRIPTION (provided by applicant): Pulmonary hypertension (PH) is a non-specific term to describe elevation in pulmonary artery (PA) pressure. Broadly, PH may be caused by elevations in left atrial pressure, increased flow through the PA and true pulmonary vascular pathology. Yet one of the most vexing problems in the ontology of PH is the presence of pressures that seem excessively high in patients with known lung and heart diseases. The current descriptors of these patients include "out of proportion" PH and "combined" disease from the World Symposium on PH in 2013. Our application focuses on patients with C-PH in the context of elevated left atrial pressure with PH that is greater than would be expected by purely passive mechanisms. Because C-PH is so poorly defined, almost nothing is known about this phenotype. C-PH is commonly found in patients with diastolic and systolic left heart dysfunction and has been associated with worse prognosis in these conditions, but we presently lack any specific therapy for C-PH. Our group has published on the differentiation of pulmonary arterial hypertension (due to pulmonary arterial remodeling, PAH) from Group II PH (passive pulmonary hypertension due to left atrial hypertension) and has studied patients with PH out of proportion to left atrial hypertension. Further we have identified metabolic syndrome associations with PH in animal models and affected patients. We have developed an infrastructure for PH patient clinical and research phenotyping including a large biobank that we have used to identify genetic variants associated with heritable pulmonary vascular disease collaboratively with other groups. We now hypothesize that genetic variants and metabolic traits contribute to development of C-PH associated with left atrial hypertension and can be exploited to define endophenotypes and dynamically identify subsets of PH patients that are likely to respond to targeted therapeutics. Our proposal includes three specific aims to test this hypothesis. First we will physiologically and clinically phenotype C-PH to demonstrate the presence of fixed pulmonary vascular disease unlike Group II PH. Second we will use forward and reverse phenotyping with whole exome sequencing, transcriptomic and metabolomic data to define a molecular classification of PAH, Group II PH and C-PH. We will confirm our findings using BioVu, a Vanderbilt DNA databank with deidentified patient information. Third, we will dynamically phenotype C-PH patients to identify those likely to respond to PAH-directed therapy. At the conclusion of these studies we will have identified common genetic and metabolic features of C-PH and used dynamic phenotyping to recognize C-PH patients likely to respond to PAH-directed therapy. These studies will form a construct for building a molecular classification of all PH and proof of concept that certain molecularly- defined phenotypes can be identified prior to treatment and guide optimal therapy.

描述（由申请人提供）：肺动脉高压（PH）是描述肺动脉（PA）压力升高的非特定术语。一般来说，PH 可能是由左心房压力升高、通过 PA 的流量增加以及真正的肺血管病变引起的。然而，肺动脉高压本体论中最令人烦恼的问题之一是患有已知肺病和心脏病的患者的压力似乎过高。目前对这些患者的描述包括“不成比例”的 PH 和 2013 年世界 PH 研讨会上的“混合”疾病。我们的应用重点是左心房压力升高且 PH 高于纯粹被动机制预期的 C-PH 患者。由于 C-PH 的定义非常不明确，因此人们对这种表型几乎一无所知。 C-PH 常见于左心舒张期和收缩期功能障碍的患者，并且与这些疾病的预后较差有关，但我们目前缺乏针对 C-PH 的任何具体治疗方法。我们小组发表了关于肺动脉高压（由于肺动脉重构，PAH）与 II 组 PH（由于左心房高压引起的被动性肺动脉高压）的区分，并研究了 PH 与左心房高压不成比例的患者。此外，我们在动物模型和受影响的患者中确定了代谢综合征与 PH 的关联。我们开发了用于肺动脉高压患者临床和研究表型分析的基础设施，包括一个大型生物库，我们用它与其他小组合作识别与遗传性肺血管疾病相关的遗传变异。我们现在假设遗传变异和代谢特征有助于与左心房高血压相关的 C-PH 的发展，并可用于定义内表型并动态识别可能对靶向治疗产生反应的 PH 患者亚群。我们的提案包括三个具体目标来检验这一假设。首先，我们将对 C-PH 进行生理和临床表型分析，以证明存在与 II 组 PH 不同的固定肺血管疾病。其次，我们将使用正向和反向表型分析以及全外显子组测序、转录组学和代谢组学数据来定义 PAH、II 组 PH 和 C-PH 的分子分类。我们将使用范德比尔特 DNA 数据库 BioVu 来确认我们的发现，其中包含未识别的患者信息。第三，我们将对 C-PH 患者进行动态表型分析，以确定那些可能对 PAH 定向治疗有反应的患者。在这些研究结束时，我们将确定 C-PH 的常见遗传和代谢特征，并使用动态表型分析来识别可能对 PAH 定向治疗有反应的 C-PH 患者。这些研究将形成一个构建结构，用于构建所有 PH 的分子分类，并证明可以在治疗前识别某些分子定义的表型并指导最佳治疗。