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

与肺动脉高压右心室衰竭和死亡率相关的蛋白质组学特征

• 批准号: 10675409
• 负责人: Hongyang Pi
• 金额: $ 8.54万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675409
• 关键词: Big Data; Bioinformatics; Biological; Biological Factors; Biological Process; Biometry; Blood Vessels; Brain natriuretic peptide; Clinical; Complement; Complex; Data; Dedications; Dimensions; Disease; Etiology; Event; Foundations; Functional disorder; Funding; Goals; Heart; Heart failure; Heterogeneity; Histidine; Histidine Metabolism Pathway; Individual; K-Series Research Career Programs; Left; Life; Link; Lung; Machine Learning; Maps; Master of Science; Mediating; Mentors; Mentorship; Metabolic; Metabolic Marker; Metabolic Pathway; Metabolism; Methodology; Methods; Molecular; Morbidity - disease rate; N-terminal; National Heart, Lung, and Blood Institute; Outcome; Participant; Pathway interactions; Patients; Phenotype; Plasma; Polyamines; Process; Progressive Disease; Proteins; Proteome; Proteomics; Pulmonary Heart Disease; Pulmonary Hypertension; Pulmonary Vascular Resistance; Research; Right Ventricular Dysfunction; Right ventricular structure; Severities; Signal Transduction; Solid; Sphingomyelins; Systems Biology; Tissues; Training Programs; Translational Research; Universities; Vascular remodeling; Ventricular; Washington; Work; candidate identification; career; cohort; data integration; experience; insight; metabolic profile; metabolome; metabolomics; mortality; multidimensional data; multiple omics; novel; prognosis biomarker; prospective; protein biomarkers; proteomic signature; pulmonary arterial hypertension; pulmonary vascular disorder; randomized trial; right ventricular failure; skills; targeted treatment; therapeutic target; tool

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.

项目摘要/摘要 肺动脉高压（PAH）是一种罕见但威胁生命的疾病，其特征是血管 肺血管抗性的重塑和逐渐升高。这些事件导致心力衰竭， 明显的发病率和高死亡率。右心（RV）词典和功能障碍的时机与 患者对患者，即使在其他相似的RV后负荷的人中；但是，生物学基础 RV适应中的这种异质性尚不清楚。识别和理解分子机制 RV不适是发现新型右心脏靶向治疗的重要步骤。 PI博士最近在使用PAH参与者的深层表型参与者中探索了血浆代谢组学特征 系统生物学方法，发现与正确指标相关的独特代谢途径和剖面 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。 重要的是要欣赏，尽管正确的心脏适应与正确的心力衰竭有关，但这是一个独特的状况。 具体而言，正确的心力衰竭可能仅代表肺动脉高压的严重程度，而正确的心脏 适应反映了正确心脏对任何严重性肺血管反应的能力或无能 疾病。调整正确心力衰竭的代谢组学分析以说明 肺血管耐药性，鞘磷脂代谢与RV适应性之间的关联 在其他相似的心脏后负荷的人中。 在此提案中，使用来自华盛顿大学的同一前瞻性观察PAH队列 旨在通过（i）识别与RV不良适应相关的蛋白质组学特征来扩展其代谢组学的工作 和PAH的死亡率； （ii）整合多矩（代谢组和蛋白质组学）信号以发现失调 与结果不佳有关的途径和特征。重要的是，科学目的直接支持 在系统生物学和生物信息学方面正在进行的持续严格的培训计划，这些计划将专门增强 蛋白质组学分析和综合OMICS方法。这个项目的成功完成将产生小说 数据和方法将为RV适应的K23提案提供稳固的基础，最终 一个独立资助的职业，利用“大数据”来了解复杂的心肺疾病。