Risk and Resilience in Pulmonary Arterial Hypertension and Genetically Susceptible Individuals

肺动脉高压和遗传易感人群的风险和恢复能力

• 批准号: 10573886
• 负责人: Eric Douglas Austin
• 金额: $ 40万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573886
• 关键词: Risk; Resilience; Pulmonary; Arterial; Hypertension

ABSTRACT Pulmonary arterial hypertension (PAH) is an orphan disease with a delayed diagnosis and markedly elevated mortality from right heart failure. Despite nearly a dozen FDA-approved drugs for PAH, median survival is only seven years. All approved therapies target one of three vasodilatory pathways, and none are disease modifying. This application has two objectives: 1) Understand dynamic and static relationships between molecular markers and PAH progression and resilience; 2) Identify molecular features of PAH risk and resilience in individuals harboring a PAH-causing mutation. It is unknown why some at risk individuals develop PAH and others do not. BMPR2 mutations are present in about 30% of patients with PAH but clinical penetrance is only 20%. Unaffected BMPR2 mutation carriers (UMCs) are a unique and understudied population that may also provide clues to disease trajectory in patients with clinical PAH. Longitudinal natural history studies with molecular profiling in PAH are lacking. Most molecular profiling studies in PAH are cross- sectional which limits understanding of how disease progression and disease markers relate over time. We propose a strategy of dense clinical and molecular phenotyping at multiple timepoints to overcome inferential limitations of cross-sectional studies. This application will leverage the clinical and research infrastructure built at Vanderbilt over the past 35 years in our study of PAH patients. The investigators share an extensive published record of recruiting patients with this rare disease and related UMCs. We hypothesize that a comprehensive understanding of risk and resilience over time in patients and genetically susceptible individuals will provide insight into disease severity and identify novel therapeutic targets in patients with PAH. Aim 1 will identify static and dynamic molecular features of disease progression and resilience. 1a: Perform serial clinical, proteomic, and gene expression profiling in HPAH, IPAH, and healthy controls 3 times over 4 years. Bioinformatic and network medicine analyses will identify proteins and RNAs associated with changes in clinical outcomes, functional capacity, and RV function in the parent cohort and two external validation cohorts. 1b: Test whether adding molecular risk/resilience markers will improve the performance of a widely used PAH risk prediction tool (REVEAL 2.0 Risk Score). Aim 2 will identify the clinical and molecular factors that promote resilience and susceptibility to PAH in a longitudinal cohort of UMCs. UMCs will undergo serial clinical and molecular phenotyping as in Aim 1. Proteins/genes that mirror PAH are “risk factors” and those that mirror a healthy population are “resilience factors”. Explanatory models will be developed and tested in validation cohorts. We will test UMC risk and resilience features for associations with clinical outcomes in PAH patients and risk prediction performance. These studies will identify signatures of risk and resilience to PAH progression and penetrance, offering an initial step toward personalizing care and surveillance guided by biologic data.

抽象的 肺动脉高压（PAH）是一种孤儿病，诊断延迟，明显升高 右心衰竭的死亡率。尽管几乎有十几种FDA批准的PAH药物，但中位生存仅是 七年。所有批准的疗法针对三种血管舒张途径之一，没有一个是疾病 修改。该应用程序有两个目标：1）了解之间的动态和静态关系 分子标记和PAH的进展和弹性； 2）确定PAH风险的分子特征和 携带引起PAH突变的个体的弹性。尚不清楚为什么有些人在风险中发展 PAH和其他人没有。 BMPR2突变存在于大约30％的PAH患者中，但临床 外渗只有20％。未受影响的BMPR2突变携带者（UMC）是独特而被理解的 在临床PAH患者中也可能为疾病轨迹提供线索的种群。纵向自然 缺乏具有PAH分子分析的历史研究。 PAH中的大多数分子分析研究是跨的 局部限制了对疾病进展和疾病标志物如何随时间相关的理解。我们 提案在多个时间点上的密集临床和分子表型的策略来克服推论 横断研究的局限性。该应用将利用临床和研究基础设施建造 在过去的35年中，我们对PAH患者的研究。调查人员分享了广泛的 发表了这种罕见疾病和相关UMC的招募患者的记录。我们假设一个 对患者的风险和弹性的全面了解，并且普遍存在 个体将洞悉疾病严重程度，并确定PAH患者的新型治疗靶标。 AIM 1将确定疾病进展和弹性的静态和动态分子特征。 1A：执行 HPAH，IPAH和健康对照的连续临床，蛋白质组学和基因表达分析超过4倍 年。生物信息学和网络医学分析将确定与变化相关的蛋白质和RNA 母体队列和两个外部验证队列中的临床结果，功能能力和RV功能。 1B：测试是否添加分子风险/弹性标记是否会改善广泛使用的PAH的性能 风险预测工具（揭示2.0风险评分）。 AIM 2将确定促进的临床和分子因素 在UMC的纵向队列中，对PAH的韧性和敏感性。 UMC将经历连续临床和 分子表型如AIM 1。反映PAH的蛋白质/基因是“危险因素”，而反射A的蛋白质/基因 健康人群是“弹性因素”。解释模型将在验证中开发和测试 同伙。我们将测试与PAH患者临床结果的关联的UMC风险和弹性特征 和风险预测性能。这些研究将确定对PAH的风险和韧性的签名 进步和外观，为迈向个性化护理和监视的第一步 生物数据。