Proteomic Signatures Associated with Right Ventricular Failure and Mortality in Pulmonary Arterial Hypertension

项目总结/摘要 肺动脉高压（PAH）是一种罕见但危及生命的疾病，其特征是血管性高血压。 重建和肺血管阻力的进行性升高。这些事件导致右心衰竭， 发病率高，死亡率高。右心室（RV）扩张和功能障碍的时间从 患者之间，甚至在其他方面具有相似RV后负荷的个体之间;然而， RV适应中的这种异质性尚不清楚。识别和理解 右心室适应不良是发现新型右心靶向治疗的重要环节。 博士Pi最近在PAH参与者的深度表型队列中探索了血浆代谢组学特征， 一种系统生物学方法，发现了不同的代谢途径和与权利指标相关的概况。 心力衰竭和死亡率。特别是，多胺和组氨酸代谢始终与 这些结果。 重要的是要认识到，虽然右心适应与右心衰竭有关，但它是一种独特的疾病。 具体而言，右心衰竭可能仅代表肺动脉高压的严重程度，而右心衰竭可能仅代表肺动脉高压的严重程度。 适应性反映右心对任何严重的肺血管疾病作出反应的能力或无能力。 疾病当调整右心衰竭的代谢组学分析以解释 肺血管阻力，鞘磷脂代谢和RV适应之间的关联出现 右心后负荷相似的个体。 在本提案中，Pi博士使用来自华盛顿大学的相同前瞻性观察性PAH队列 旨在通过（i）鉴定与RV适应不良相关的蛋白质组学特征， 和死亡率;（ii）整合多组学（代谢组学和蛋白质组学）信号， 与不良结局相关的途径和特征。重要的是，科学目标直接支持 正在进行的系统生物学和生物信息学的严格培训计划，将专门提高 蛋白质组学分析和整合组学方法。该项目的成功完成将产生新的 这些数据和方法将为K23提案提供坚实的基础，该提案侧重于RV适应， 一个独立资助的职业，利用“大数据”来了解复杂的心肺疾病。

PROJECT SUMMARY/ABSTRACT Pulmonary arterial hypertension (PAH) is a rare but life-threatening disease characterized by vascular remodeling and progressive elevation in pulmonary vascular resistance. These events result in right heart failure, significant morbidity, and a high mortality. The timing of right ventricular (RV) dilation and dysfunction varies from patient to patient, even among individuals with otherwise similar RV afterload; however, the biological basis for this heterogeneity in RV adaptation is not yet known. Identifying and understanding molecular mechanisms of RV maladaptation are important steps for discovering novel right heart targeted therapy. Dr. Pi recently explored plasma metabolomic signatures in a deeply phenotyped cohort of PAH participants using a systems biology approach and found distinct metabolic pathways and profiles associated with metrics of right heart failure and mortality. In particular, polyamine and histidine metabolism were consistently associated with these outcomes. It is important to appreciate that while right heart adaptation is related to right heart failure, it is a distinct condition. Specifically, right heart failure may merely represent the severity of pulmonary hypertension, while right heart adaptation reflects the ability or inability of the right heart to respond to any severity of pulmonary vascular disease. When the metabolomics analyses of right heart failure were adjusted to account for differences in pulmonary vascular resistance, an association between sphingomyelin metabolism and RV adaptation emerged in individuals with otherwise similar right heart afterload. Using the same prospective observational PAH cohort from University of Washington, in this proposal Dr. Pi aims to extend her metabolomics work by (i) identifying proteomic profiles associated with RV maladaptation and mortality in PAH; (ii) integrating the multi-omic (metabolomic and proteomic) signals to find dysregulated pathways and features associated with poor outcomes. Importantly, the scientific aims directly support an ongoing and rigorous training program in systems biology and bioinformatics that will specifically enhance the proteomic analysis and integrative omics approaches. Successful completion of this project will generate novel data and methods that will provide a solid foundation for a K23 proposal focused on RV adaptation and ultimately an independently funded career leveraging “big data” to understand complex cardiopulmonary disease.