Genomics of Pulmonary Vascular Disease

肺血管疾病的基因组学

• 批准号: 10593913
• 负责人: Micheala A Aldred
• 金额: $ 85.45万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593913
• 关键词: Affect; Arteriovenous malformation; Award; Blood; Blood Cells; Blood Vessels; Bone Morphogenetic Proteins; Brain; Cardiac Catheterization Procedures; Catheters; Cells; Chromosome abnormality; Complex; DNA Damage; DNA analysis; Data; Defect; Diagnosis; Disease; Disease Progression; Endothelial Cells; Etiology; Evolution; Funding; Genetic; Genetic Variation; Genomics; Goals; Heart failure; Hemorrhage; Hereditary hemorrhagic telangiectasia; In Vitro; Inherited; Leadership; Life; Liver; Lung; Molecular; Morbidity - disease rate; Mutation; National Heart, Lung, and Blood Institute; Nonsense Mutation; Orphan Drugs; Pathway interactions; Patients; Pharmaceutical Preparations; Precision therapeutics; Prevention; Pulmonary Hypertension; Reactive Oxygen Species; Research; Research Personnel; Resolution; Ribosomes; Risk; Signal Pathway; Signaling Protein; Somatic Mutation; Stroke; Structure of parenchyma of lung; Technology; Testing; Vascular Diseases; Vascular remodeling; Work; diagnostic signature; disorder prevention; improved; innovation; mouse model; next generation sequencing; novel; novel diagnostics; novel therapeutic intervention; novel therapeutics; prognostic signature; programs; public health relevance; pulmonary arterial pressure; pulmonary artery endothelial cell; pulmonary vascular disorder; pulmonary vascular remodeling; response; right ventricular failure; single cell sequencing; small molecule

PROJECT SUMMARY Pulmonary hypertension (PH) is a potentially fatal disease characterized by progressive pulmonary vascular remodeling and elevated pulmonary artery pressure, leading to right heart failure. The molecular etiology is poorly understood, even in familial PH where mutations in the bone morphogenetic protein (BMP) signaling pathway are well characterized. Our approach focuses on understanding the germline genetic variation that predisposes to PH, and somatic changes within the lung that may contribute to the onset and/or progression of the disease. We were the first to identify chromosome abnormalities in pulmonary artery endothelial cells from explant PH lung tissue. Levels of DNA damage were higher in lung and blood cells from patients than controls, and correlated with the amount of reactive oxygen species. Similar changes were found in the blood of patients' relatives, suggesting this may be genetically determined. Our current studies utilize state of the art next generation sequencing approaches in lung tissues and cells to test the hypothesis that increased levels of DNA damage predispose to genetic alterations in the lung, and may contribute to vascular remodeling in PH. We are also testing novel therapeutic approaches to correct BMP signaling in familial PH and hereditary hemorrhagic telangiectasia (HHT), a related vascular disorder also caused by mutations in the BMP pathway. HHT carries high morbidity associated with risk of hemorrhage from arteriovenous malformations in the lungs, liver and brain. Our current studies focus on ataluren, a small molecule with orphan drug status that promotes ribosomal readthrough of nonsense mutations. In preliminary studies, BMP signaling was restored in cells from 5 of 6 patients with different nonsense mutations. In vitro studies in blood or lung-derived endothelial cells from affected patients are complimented with treatment and prevention studies in a genetic mouse model. This Outstanding Investigator Award proposal combines these two major themes into a unified research program in the genomics of pulmonary vascular disease. We will harness the emerging power of single cell sequencing technologies to develop novel analyses of endothelial cells that adhere to the Swan-Ganz catheter after routine cardiac catheterization. This will extend our current studies in several new directions: (1) enabling direct analysis of DNA damage markers in disease-relevant cells; (2) providing immediate ex vivo readouts of drug responses; (3) developing novel diagnostic and prognostic signatures; and (4) perhaps ultimately providing single cell resolution of the timing and evolution of somatic mutations in the PH lung. Through leadership in the genomics components of two NHLBI-funded national consortia, we will leverage the results of these innovative studies and integrate them with a broad range of other omics data to realize the goals of improving the diagnosis, precision treatment and ultimate prevention of pulmonary vascular disease.

项目概要 肺动脉高压（PH）是一种潜在致命的疾病，其特征是进行性肺血管病变 重塑和肺动脉压力升高，导致右心衰竭。分子病因学是 人们对此知之甚少，即使是在骨形态发生蛋白 (BMP) 信号突变的家族性 PH 中 途径得到了很好的表征。我们的方法侧重于了解种系遗传变异 易患 PH 和肺内的体细胞变化，可能导致肺结核的发作和/或进展 这种疾病。我们是第一个发现肺动脉内皮细胞染色体异常的人 外植 PH 肺组织。患者肺细胞和血细胞中的 DNA 损伤水平高于对照组， 并与活性氧的含量相关。血液中也发现了类似的变化 患者的亲属表明这可能是由基因决定的。我们目前的研究利用最先进的技术 肺组织和细胞中的下一代测序方法来检验以下假设： DNA 损伤容易导致肺部基因改变，并可能导致肺动脉高压中的血管重塑。 我们还在测试新的治疗方法，以纠正家族性 PH 和遗传性 BMP 信号传导 出血性毛细血管扩张症 (HHT) 是一种相关的血管疾病，也是由 BMP 通路突变引起的。 HHT 的发病率很高，与肺部动静脉畸形出血的风险相关， 肝脏和大脑。我们目前的研究重点是 ataluren，一种具有孤儿药地位的小分子，可促进 无义突变的核糖体通读。在初步研究中，BMP 信号在来自以下细胞的细胞中恢复： 6 名患者中有 5 名具有不同的无义突变。血液或肺源性内皮细胞的体外研究 来自受影响患者的基因小鼠模型的治疗和预防研究得到了称赞。 这项杰出研究者奖提案将这两个主要主题结合成一个统一的研究 肺血管疾病基因组学计划。我们将利用单细胞的新兴力量 测序技术对粘附在 Swan-Ganz 导管上的内皮细胞进行新的分析 常规心导管检查后。这将把我们当前的研究扩展到几个新的方向：（1） 直接分析疾病相关细胞中的 DNA 损伤标记； (2) 立即提供离体读数 药物反应； (3) 开发新的诊断和预后特征； (4) 也许最终 提供 PH 肺中体细胞突变的时间和进化的单细胞分辨率。通过 由于我们在两个 NHLBI 资助的国家联盟的基因组学领域处于领先地位，我们将利用 这些创新研究并将其与广泛的其他组学数据相结合，以实现以下目标： 提高肺血管疾病的诊断、精准治疗和最终预防水平。