Genomic and Circulating Predictors of PAH response

PAH 反应的基因组和循环预测因子

基本信息

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
项目类别：
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

项目摘要

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松弛疾病，其特征是血管异常，右心力衰竭和死亡。尽管PAH的三堂课中有十种FDA批准的疗法，但没有治愈性，大约40％的患者在诊断后的5年内死亡。没有识别将对特定疗法做出反应的患者和许多患者的既定方法等待有效的疗法时恶化。该提议的目标是改善 PAH通过先进的遗传学和“ OMICS”方法使用精密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的同类中患者，有两个子集对治疗有罢工反应。一个是一个有一个的小子集肺动脉压力明显降低，响应血管扩张剂和戏剧性对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的外围血液转录组和基因组特征反应将他们与无反应性患者区分开来的患者。第二个子集是患者父母前列环素治疗的明显改善。我们和其他人报告了肺动脉压的标准化，一部分由父母治疗的PAH患者前列环素治疗。在初步数据中，我们确定了长期生存的临床预测指标对父母前列环素治疗的反应，并发现了分化的转录模式这些患者。我们还确定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受体的抑制。我们有初步的确定了调节前列环素受体表达并区分患者的遗传变异对前列环蛋白治疗的反应良好和不良反应。这些数据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的响应能力，可以探索以了解药物效率的机制和优化患者护理。在这笔赠款中，我们建议1）了解有助于 PAH中对前列环蛋白治疗的差异临床反应，2）识别外周血衍生的emic 鉴定对父母前列环素治疗持续临床反应的患者的概况，3）前瞻性地测试我们的遗传和OMIC特征能力，以预测 PH临床治疗PP的PROSTACYCLIN治疗。该提议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。