Molecular pathogenesis of pulmonary arterial hypertension

项目总结/摘要 肺动脉高压（PAH）是一种罕见的疾病，其特征是进行性肺动脉重构， 肺动脉（PA）。它是不可治愈的，并导致死亡的右心室心力衰竭在3年内，如果 未经治疗。骨形态发生蛋白2型受体基因（BMPR 2）的杂合突变是骨形成蛋白2型受体基因（BMPR 2）的突变。 遗传性和非遗传性PAH的主要遗传原因。与无BMPR 2的患者相比 BMPR 2突变的PAH患者至少提前10年发生更严重的PAH。 尽管在了解介导闭塞性重构的分子和细胞过程方面取得了进展， 作为BMPR 2突变的结果，靶向治疗尚不存在，BMPR 2携带者患者仍然存在 需要移植的风险很高，并死于这种疾病。我们迫切需要新的治疗方法 BMPR 2突变的患者。 我们的研究表明，特发性和遗传性PAH患者的DNA损伤增加， 这表明遗传毒性应激是PAH的一个风险因素，但仍然存在重大的知识差距，如下所示：（i） 基因组完整性的丧失是PAH的原因还是结果，（ii）DNA 损伤发生，（iii）BMPR 2突变和DNA损伤之间的潜在联系，以及（iv）分子 PAH的DNA损伤机制。我们发现，BMPR 2及其下游信号通路是 对于保护肺动脉内皮细胞（PAECs）的基因组完整性至关重要，它们通过 维持DNA修复途径的关键成分：Rad 51。BMPR 2的失活导致 Rad 51，导致PAEC中DNA损伤的积累。Rad 51的衰减是在 PAH动物模型和人类患者的内皮。相反，BMPR 2的激活 BMP 9通过信号通路恢复Rad 51并防止PAEC中DNA损伤的积累。的 我们将检验的主要假设是，经历遗传毒性应激的PAEC发生病理性重塑， 呸。本申请的目的是开发一种恢复PAEC中DNA修复系统的策略， 预防或抑制血管重塑的进展，作为BMP缺陷型PAH的新疗法 信号了即将到来的结果，从这个应用程序将提供重要的见解，开发一种新的 PAH的治疗策略。

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.