Genomic and Circulating Predictors of PAH response

PAH 反应的基因组和循环预测因子

• 批准号: 10166908
• 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/10166908
• 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 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.

摘要 肺动脉高压是一种以血管闭塞为特征的顽固性疾病，对吗？ 心力衰竭和死亡。尽管FDA批准了三类10种治疗PAH的方法， 没有一种是治愈的，大约40%的患者在确诊后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 在等待有效治疗的同时病情恶化。这项提案的目标是改善#年的成果 PAH通过先进的遗传学和OMICS方法使用精准医学的概念 融合了转录组学、蛋白质组学和代谢组学。在未选择的多环芳烃队列中 患者中，有两个亚组对治疗有显著反应。一种是一个子集，它有一个 对血管扩张剂的反应使肺动脉压显著降低 钙通道阻滞剂治疗的长期临床反应。我们最近发表了 钙通道阻滞剂反应性外周血转录和基因组特征 患者将他们与无反应的患者区分开来。第二个子组是那些有 前列环素肠外治疗效果显著。我们和其他人已经报道了 部分接受胃肠外治疗的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存活的临床预测因素 对非肠道前列环素治疗的反应，并发现了不同的转录模式 这些病人。我们还鉴定了前列环素受体表达的变异性。 对照组的淋巴母细胞与PAH中受体的抑制。我们已经初步完成了 识别调节前列环素受体表达并区分患者的基因变异 对前列环素治疗有好有差的反应。这些数据构成了我们假设的基础 外周血源性遗传和基因组图谱确定了前列环素的相关性 多环芳烃的反应性，可被用来理解药物疗效的机制和 优化患者护理。在这笔赠款中，我们建议1)了解基因变异对 前列环素治疗PAH的不同临床反应：2)鉴定外周血源性基因组 确定对前列环素治疗有持久临床反应的患者的资料，3) 前瞻性地测试我们的基因和基因组图谱预测短期反应的能力 PPS治疗PAH的前列环素治疗这项提议的长期目标是 更好地将患者独特的生物学与PP疗法相匹配，潜在地提高了患者的存活率 病态的疾病。