Genomic and Circulating Predictors of PAH response

PAH 反应的基因组和循环预测因子

• 批准号: 9926307
• 负责人: Anna R Hemnes
• 金额: $ 62.21万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926307
• 关键词: Achievement; Acute; Address; Biological; Biology; Blood Vessels; Blood specimen; Calcium Channel Blockers; Cessation of life; Clinical; Cyclic AMP; DNA; Data; Diagnosis; Disease; Enrollment; FDA approved; Future; Genes; Genetic; Genetic Determinism; Genetic Transcription; Genetic Variation; Genomics; Genotype; Goals; Grant; Heart failure; Individual; Link; Lung; Measures; Mediating; Mediator of activation protein; Medical Records; Methodology; Molecular; Ontology; Outcome; Pathway interactions; Patient Care; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Prevalence; Production; Prostaglandins I; Proteomics; Publishing; Pulmonary artery structure; RNA; Receptor Activation; Receptor Gene; Reporting; Sampling; Selection for Treatments; Severity of illness; Signal Transduction; Single Nucleotide Polymorphism; Techniques; Testing; Variant; Vasodilator Agents; base; biobank; clinical predictors; cohort; drug efficacy; drug response prediction; effective therapy; endothelial stem cell; exome sequencing; experimental study; genetic predictors; genetic profiling; genetic variant; genomic signature; hemodynamics; improved; improved outcome; individual patient; insight; metabolomics; patient response; peripheral blood; precision medicine; pressure; prospective; prospective test; pulmonary arterial hypertension; receptor; receptor expression; response; transcriptomics

SUMMARY Pulmonary arterial hypertension is a relentless disease characterized by vascular obliteration, right heart failure and death. Although there are ten FDA-approved therapies in three classes for PAH, none is curative and approximately 40% of patients are dead within 5 years of diagnosis. There is no established approach to identify patients who will respond to a specific therapy and many patients worsen while waiting for an effective therapy. The goals of this proposal are to improve outcomes in PAH using the concepts of precision medicine through an advanced genetics and “Omics” approach incorporating transcriptomics, proteomics and metabolomics. Within cohorts of unselected PAH patients, there are two subsets with striking responses to therapy. One is a small subset that has a marked reduction in pulmonary artery pressure acutely in response to vasodilators and a dramatic long-term clinical response to calcium channel blocker therapy. We have recently published peripheral blood transcriptomic and genomic signatures of calcium channel blocker responsive patients differentiating them from non-responsive patients. The second subset is patients that have marked improvement with parenteral prostacyclin therapy. We and others have reported normalization of pulmonary arterial pressure in a subset of PAH patients treated with parenteral prostacyclin therapy. In preliminary data, we have identified clinical predictors of long-term survival in response to parenteral prostacyclin therapy and have found transcriptomic patterns that differentiate these patients. We have also identified variability in expression of the prostacyclin receptor in lymphoblastoids of control individuals and suppression of the receptor in PAH. We have preliminarily identified genetic variants that regulate prostacyclin receptor expression and that differentiate patients with good and poor responses to prostacyclin therapy. These data form the basis of our hypothesis that peripheral blood-derived genetic and Omic profiles identify correlates of prostacyclin responsiveness in PAH and can be exploited to understand mechanisms of drug efficacy and to optimize patient care. In this grant we propose to 1) understand genetic variation contributing to differential clinical response to prostacyclin therapy in PAH, 2) identify peripheral blood-derived Omic profiles to identify patients with durable clinical responses to parenteral prostacyclin therapy, 3) prospectively test our genetic and Omic profiles capacity to predict short-term responses to prostacyclin therapy in PAH clinically treated with PPs. The long term goals of this proposal are to better match a patient's unique biology to PP therapy, potentially improving survival in this highly morbid disease.

概括 肺动脉高压是一种以血管闭塞为特征的持续性疾病，右 心力衰竭和死亡。尽管 FDA 批准了三类 10 种 PAH 疗法， 没有一种方法可以治愈，大约 40% 的患者在诊断后 5 年内死亡。没有 确定对特定治疗有反应的患者和许多患者的既定方法 在等待有效治疗期间病情恶化。该提案的目标是改善结果 PAH 通过先进的遗传学和“组学”方法运用精准医学的概念 结合转录组学、蛋白质组学和代谢组学。在未选择的 PAH 队列中 在患者中，有两个亚群对治疗有显着的反应。一个是一个小子集，具有 对血管扩张剂的反应导致肺动脉压力急剧下降，并且显着降低 对钙通道阻滞剂治疗的长期临床反应。我们最近发布了 钙通道阻滞剂反应的外周血转录组和基因组特征 患者将其与无反应患者区分开来。第二个子集是患有以下疾病的患者 肠外前列环素治疗有显着改善。我们和其他人已经报道过 部分接受肠外治疗的 PAH 患者的肺动脉压正常化 前列环素治疗。在初步数据中，我们已经确定了长期生存的临床预测因素 对肠外前列环素治疗的反应，并发现了区分的转录组模式 这些病人。我们还发现了前列环素受体表达的变异性 对照个体的淋巴母细胞和 PAH 中受体的抑制。我们已经初步 确定了调节前列环素受体表达并区分患者的基因变异 对前列环素治疗的反应有好有坏。这些数据构成了我们假设的基础 外周血来源的遗传和组学图谱确定了前列环素的相关性 PAH 的反应性，可用于了解药物功效机制并 优化患者护理。在这笔赠款中，我们建议 1）了解遗传变异有助于 PAH 患者对前列环素治疗的不同临床反应，2) 确定外周血来源的 Omic 以确定对肠外前列环素治疗有持久临床反应的患者，3) 前瞻性地测试我们的基因和组学特征预测短期反应的能力 临床上用 PP 治疗的 PAH 中的前列环素治疗。该提案的长期目标是 更好地将患者独特的生物学特性与 PP 疗法相匹配，有可能提高这种高度生存的生存率 病态的疾病。