A molecular phenotype of combined pulmonary hypertension

合并性肺动脉高压的分子表型

• 批准号: 8796005
• 负责人: Anna R Hemnes
• 金额: $ 23.55万
• 依托单位: VANDERBILT UNIVERSITY
• 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/8796005
• 关键词: Affect; Animal Model; Blood; Blood Vessels; CAV1 gene; Classification; Clinical; Clinical Data; Clinical Research; Complex; Confusion; Coupled; DNA Databases; Data; Descriptor; Development; Discriminant Analysis; Discrimination; Disease; Enrollment; Epidemiology; Evaluation; Frequencies; Functional disorder; Gene Expression Profile; General Population; Genetic; Genetic Predisposition to Disease; Genetic Transcription; Genomics; Goals; Heart; Heart Atrium; Heart Diseases; High Prevalence; Hypertension; Insulin Resistance; Knowledge; Lead; Left; Link; Liquid substance; Lung; Lung diseases; Magnetic Resonance Imaging; Measures; Medical; Metabolic; Metabolic syndrome; Methodology; Molecular; Mutation; 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; endophenotype; exome sequencing; genetic variant; hemodynamics; improved; medical specialties; metabolomics; molecular phenotype; outcome forecast; peripheral blood; pressure; pulmonary arterial hypertension; response; symposium; therapeutic target; tool; trait; 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）压力升高的非特异性术语。广义上，pH值可能是由左心压升高，流经PA的流量增加以及真正的肺血管病理。然而，在pH的本体论中，最令人烦恼的问题之一是存在已知肺和心脏病患者的压力似乎过高。这些患者的当前描述源包括2013年世界pH ph的“不合比例”和“联合”疾病。我们的应用集中于在较高的左心压升高的情况下，pH的患者的pH为pH，而pH的pH值比纯粹被动机制所期望的要大。因为C-PH的定义很差，所以几乎没有关于这种表型的知识。 C-PH通常在舒张期和收缩期左心功能障碍的患者中发现，并且在这些疾病的预后较差，但目前我们缺乏C-PH的任何特定疗法。我们的小组已经发表了关于肺动脉高压的分化（由于肺动脉重塑，PAH，PAH）（左心室高血压引起的无源肺动脉高压），并研究了与左心房高血压成比例的患者。此外，我们已经确定了动物模型中pH的代谢综合征关联，并影响了患者。我们已经开发了一种用于pH患者临床和研究表型的基础设施，包括大型生物库，我们用来鉴定与其他组合作与可遗传性肺血管疾病相关的遗传变异。现在，我们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，并且可以利用以定义内型型，并动态识别可能对靶向治疗剂反应的pH患者的子集。我们的建议包括三个特定的目的，以检验这一假设。首先，我们将在生理和临床表型C-PH上证明存在固定肺血管疾病的存在，这与II组pH不同。其次，我们将使用整个外显子组测序，转录组和代谢组数据使用前向和反向表型来定义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确认我们的发现，并具有更识别的患者信息。第三，我们将动态表型C-PH患者确定可能对PAH指导治疗的反应的患者。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，并使用动态表型来识别可能对PAH导向治疗反应的C-PH患者。这些研究将形成一种构建所有pH的分子分类的构造，并构成了所有概念证明，即可以在治疗前确定某些分子定义的表型并指导最佳治疗。