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

项目摘要/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 肺血管阻力重塑和进行性升高。这些事件会导致右心衰竭， 发病率高，死亡率高。右室(RV)扩张和功能障碍的时间不同 患者之间，即使在其他方面具有相似的RV后负荷的个体中；然而， 这种RV适应的异质性尚不清楚。识别和理解细胞毒性的分子机制 右室适应不良是发现新的右心靶向治疗的重要步骤。 Pi博士最近研究了PAH参与者的深度表型队列中的血浆代谢特征。 一种系统生物学方法，发现了与正确的指标相关的不同的代谢途径和特征 心力衰竭和死亡率。特别是，多胺和组氨酸代谢一直与 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，但它是一种截然不同的情况。 具体地说，右心衰竭可能仅代表肺动脉高压的严重程度，而右心 适应反映了右心对任何严重的肺血管反应的能力或不能。 疾病。当右心衰竭的代谢组学分析被调整以考虑到 肺血管阻力，鞘磷脂代谢和RV适应之间的联系出现了 其他方面右心后负荷相似的个体。 在这项提案中，使用了来自华盛顿大学的相同的前瞻性观察PAH队列，Pi博士 旨在通过(I)确定与RV适应不良相关的蛋白质组图谱来扩展她的代谢组学工作 和死亡率；(Ii)整合多组体(代谢组和蛋白质组)信号以发现失调 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 持续和严格的系统生物学和生物信息学培训计划，将特别增强 蛋白质组学分析和综合组学方法。该项目的成功完成将产生新的 数据和方法将为K23提案提供坚实的基础，重点是房车适应并最终 一份独立资助的职业生涯，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.