Molecular pathogenesis of pulmonary arterial hypertension

项目摘要/摘要 摘要肺动脉高压(PAH)是一种罕见的疾病，其特征是血管的进行性重构。 肺动脉(PA)。它是无法治愈的，如果发生以下情况，将在3年内死于右心衰竭。 未经治疗。骨形态发生蛋白2型受体基因(BMPR2)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。 尽管对介导血管闭塞重塑的分子和细胞过程的了解取得了进展 由于BMPR2突变导致的PAS，靶向治疗尚不存在，BMPR2携带者患者仍在 有很高的风险需要移植并死于这种疾病。迫切需要新的治疗方法。 适用于BMPR2突变患者。 我们的研究表明，特发性和遗传性PAH患者的DNA损伤都增加了， 提示基因毒性应激是PAH的危险因素，但仍然存在显著的知识差距，如下所示：(I) 基因组完整性的丧失是PAH的原因还是后果，(Ii)DNA 损伤发生，(Iii)BMPR2突变和DNA损伤之间的潜在联系，以及(Iv)分子 多环芳烃的DNA损伤机制。我们发现BMPR2及其下游信号通路是 对于保护肺动脉内皮细胞(PAECs)的基因组完整性是必不可少的，它们通过 维持DNA修复途径的一个关键组成部分：RAD51。BMPR2的失活会导致 RAD51，导致肺内皮细胞DNA损伤积累。RAD51的衰减量是在 PAH动物模型和人类患者的内皮细胞。相反，BMPR2的激活 BMP9通过信号通路恢复RAD51，防止DNA损伤在肺内皮细胞中积累。这个 我们将检验的主要假设是，承受遗传毒性应激的PAECs会发生病理性重构，并 啊哈。该应用程序的目标是开发一种策略来恢复PAEC中的DNA修复系统 预防或抑制血管重塑的进展，作为治疗BMP缺陷的PAH的新方法 信号。即将到来的这项申请的结果将为开发一种新的 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.