A molecular phenotype of combined pulmonary hypertension

描述(由申请人提供)：肺动脉高压(PH)是一个非特定术语，用于描述肺动脉(PA)压力的升高。从广义上讲，肺动脉高压可能是由左房压力升高、通过肺动脉的流量增加以及真正的肺血管病变引起的。然而，在PH的本体论中，最令人烦恼的问题之一是，在已知的肺病和心脏病患者中，压力似乎过高。目前对这些患者的描述包括2013年世界PH研讨会上的“比例失调”PH和“合并症”。我们的应用主要集中在左房压力升高的C-PH患者，其PH大于纯被动机制的预期。由于C-PH的定义非常模糊，对这种表型几乎一无所知。C-PH常见于舒张期和收缩期左心功能不全的患者，在这些情况下预后较差，但我们目前缺乏任何针对C-PH的特效治疗方法。我们小组发表了关于肺动脉高压(由于肺动脉重塑，PAH)和第二组PH(由左房高压引起的被动性肺动脉高压)的区别的文章，并研究了PH与左房高血压比例不成比例的患者。此外，我们还在动物模型和受影响的患者中确定了代谢综合征与PH的关系。我们已经开发了一个用于PH患者临床和研究表型分型的基础设施，包括一个大型生物库，我们已经使用该库与其他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房高血压相关的C-PH的发展，并可用于定义内表型和动态识别可能对靶向治疗有效的PH患者亚群。我们的建议包括三个具体目标，以检验这一假设。首先，我们将从生理和临床表型C-PH来证明存在不同于II组PH的固定性肺血管疾病。其次，我们将使用正向和反向表型结合整个外显子组测序、转录和代谢数据来定义PAH、II组PH和C-PH的分子分类。我们将使用BioVu来确认我们的发现，BioVu是一个包含已确认患者信息的Vanderbilt DNA数据库。第三，我们将动态分型C-PH患者，以确定那些可能对PAH指导的治疗有反应的患者。在这些研究的结论中，我们将确定C-PH的共同遗传和代谢特征，并使用动态表型来识别可能对PAH指导的治疗有反应的C-PH患者。这些研究将形成一个构建所有PH的分子分类的结构，并证明某些分子定义的表型可以在治疗前被识别出来，并指导最佳治疗。

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.