Molecular pathogenesis of pulmonary arterial hypertension

肺动脉高压的分子发病机制

基本信息

批准号：
10211271
负责人：
Akiko Hata
金额：
$ 80.37万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10211271
关键词：
Animal Model Attenuated Blood Cells Blood Vessels Bone Morphogenetic Proteins Cell physiology Cells Cessation of life DNA Damage DNA Double Strand Break DNA Repair DNA Repair Pathway Disease Distal Endothelium Etiology Genes Genetic Genomic Instability Genotoxic Stress Goals Heart failure Heritability Homeostasis Human Knowledge Light Link Lung Maintenance Measures Mediating Messenger RNA Molecular Morbidity - disease rate Mutation Other Genetics Pathogenesis Pathologic Patients Penetrance Progressive Disease Pulmonary artery structure Rare Diseases Receptor Gene Regulation Reporting Risk Factors Role Signal Pathway Signal Transduction Somatic Mutation System Testing Translating Transplantation Vascular Diseases Vascular remodeling Ventricular attenuation bone morphogenetic protein receptors cell type genome integrity genotoxicity high risk homologous recombination insight mortality mutation carrier novel therapeutic intervention novel therapeutics prevent primary pulmonary hypertension protein degradation pulmonary arterial hypertension pulmonary artery endothelial cell targeted treatment

项目摘要

PROJECT SUMMARY/ABSTRACT Pulmonary Arterial Hypertension (PAH) is a rare disease characterized by the progressive remodeling of pulmonary arteries (PAs). It is incurable and leads to death from right ventricular heart failure in 3 years if untreated. Heterozygous mutations of the bone morphogenetic protein type 2 receptor gene (BMPR2) are the leading genetic cause of both heritable and non-heritable PAH. Compared to patients without BMPR2 mutations, PAH patients with BMPR2 mutations develop a more severe form of PAH at least 10 years earlier. Despite the progress in understanding the molecular and cellular processes mediating occlusive remodeling of PAs as a result of BMPR2 mutations, a targeted therapy does not yet exist, and BMPR2 carrier patients remain at high risk of requiring transplantation and succumbing to the disease. There is a dire need of novel therapies for BMPR2 mutation patients. Our studies demonstrated increased DNA damage in both idiopathic- and heritable-PAH patients, suggesting genotoxic stress is a risk factor for PAH, but significant knowledge gaps persist, as follows: (i) whether the loss of genome integrity is the cause or the consequence of PAH, (ii) the cell type in which DNA damage occur, (iii) a potential link between BMPR2 mutations and DNA damage, and (iv) the molecular mechanism of DNA damage in PAH. We found that BMPR2 and its downstream signaling pathway are essential to protect genome integrity in pulmonary artery endothelial cells (PAECs), and they act by maintaining a key component of the DNA repair pathway: Rad51. Inactivation of BMPR2 results in reduction of Rad51, leading to accumulation of DNA damage in PAECs. Attenuation of Rad51 was measured in the endothelium of both animal models of PAH and human patients. On the contrary, activation of the BMPR2 signaling pathway by BMP9 restores Rad51 and prevents the accumulation of DNA damage in PAECs. The main hypothesis we will test is that PAECs undergoing genotoxic stress develop a pathological remodeling and PAH. The objective of this application is to develop a strategy to restore the DNA repair system in PAECs and prevent or inhibit the progression of vascular remodeling, as a novel therapy for PAH with a defective BMP signal. The forthcoming results from this application will provide important insights into developing a novel therapeutic strategy for PAH.

项目概要/摘要肺动脉高压（PAH）是一种罕见疾病，其特征是肺动脉进行性重塑。肺动脉（PA）。如果出现以下情况，该病是无法治愈的，并会在 3 年内因右心室心力衰竭而死亡未经治疗。骨形态发生蛋白 2 型受体基因 (BMPR2) 的杂合突变是遗传性和非遗传性 PAH 的主要遗传原因。与没有 BMPR2 的患者相比 BMPR2 突变的 PAH 患者至少提前 10 年患上更严重的 PAH。尽管在理解介导闭塞重塑的分子和细胞过程方面取得了进展 BMPR2突变导致的PA，目前尚不存在靶向治疗，BMPR2携带者患者仍然存在需要移植并死于该疾病的风险很高。迫切需要新疗法对于 BMPR2 突变患者。我们的研究表明，特发性和遗传性 PAH 患者的 DNA 损伤均增加，表明基因毒性应激是 PAH 的一个危险因素，但仍然存在重大的知识差距，如下：(i) 基因组完整性的丧失是 PAH 的原因还是结果，(ii) DNA 所在的细胞类型损伤发生，(iii) BMPR2 突变和 DNA 损伤之间的潜在联系，以及 (iv) 分子 PAH 中 DNA 损伤的机制。我们发现BMPR2及其下游信号通路对于保护肺动脉内皮细胞（PAEC）基因组完整性至关重要，它们的作用是维持 DNA 修复途径的关键组成部分：Rad51。 BMPR2 失活会导致 Rad51，导致 PAEC 中 DNA 损伤的积累。 Rad51 的衰减是在 PAH 动物模型和人类患者的内皮细胞。相反，BMPR2 的激活 BMP9 信号通路可恢复 Rad51 并防止 PAEC 中 DNA 损伤的积累。这我们将测试的主要假设是，经历基因毒性应激的 PAEC 会发生病理性重塑，并且多环芳烃。本申请的目的是制定一种策略来恢复 PAEC 中的 DNA 修复系统和预防或抑制血管重塑的进展，作为 BMP 有缺陷的 PAH 的新疗法信号。该应用即将得出的结果将为开发一种新颖的方法提供重要的见解 PAH 的治疗策略。