Genomic and Circulating Predictors of PAH response

PAH 反应的基因组和循环预测因子

• 批准号: 10393072
• 负责人: Anna R Hemnes
• 金额: $ 17.12万
• 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/10393072
• 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.

概括 肺动脉高压是一种无情的疾病，其特征是血管闭塞，正确 心力衰竭和死亡。 没有治愈性，大约40％的患者在诊断的5年内。 识别将对特定和许多患者做出反应的患者的既定方法 在等待有效的疗法的过程中恶化。 PAH通过先进的遗传学和“ OMICS”方法使用精密医学的概念 在未选择的PAH中纳入转录组学，蛋白质组学和代谢组学。 患者是您两个子集，对治疗有惊人的反应。 对血管扩张剂的急性急性和剧烈的肺动脉压力进行了明显的修复 对钙通道阻滞剂治疗的长期临床反应。 钙通道阻滞剂的外围血液转录组和基因组特征反应 将他们与非反应性患者区分开来的患者。 父母的前列腺素治疗明显改善。 用肠胃外治疗的患者子集的肺动脉压的归一化 前列环蛋白治疗。 对段落前列环素治疗的反应，并发现了分化的转录组模式 这些患者。 对照个体的淋巴细胞和PAH的受体抑制 确定调节前列环蛋白表达和区分的遗传变异 对前列环蛋白治疗的良好和池的反应构成了我们假设的基础 外围血液衍生的遗传和OMIC特征鉴定了前列环蛋白的相关性 PAH的启发性，可以利用以了解药物疗效的机制和 优化患者护理。 PAH治疗中对前列环蛋白的差异临床反应，2）识别外周血衍生的OMIC 剖面以鉴定对段落前列环素治疗的持续临床反应的患者，3） 前瞻性地测试我们的遗传和OMIC特征能力，以预测 PPS临床治疗的PROSTACYCLIN治疗该提案的长期目标是。 更好地将患者的独特生物学与PP疗法相匹配，这可能会改善这种高度的生存率 病态疾病。