研究证实骨形态发生蛋白Ⅱ型受体(BMPRⅡ)突变导致肺动脉高压的发生, 而先天性心脏病肺动脉高压(CHD/PAH) BMPRⅡ突变率最低，但其BMP信号通路显著下调且机制不明。本研究通过蛋白抗体芯片筛选发现CHD/PAH患者BMP拮抗因子NBL1血浆浓度显著升高；组织化学显示CHD/PAH重构的肺血管强表达NBL1，因此推测升高的NBL1通过拮抗BMP参与CHD/PAH进程。本研究拟探讨: ①在持续的体-肺分流刺激下，大鼠肺组织NBL1和BMP信号通路表达水平的变化及NBL1血浆浓度与肺血流动力学指标和肺血管重构程度的相关性；②NBL1抑制BMP活性，调节人肺动脉内皮和平滑肌细胞增殖、迁移、凋亡及对BMP信号通路的影响；③在体阻断NBL1对PAH的影响。本研究旨在揭示NBL1参与CHD/PAH肺血管重构的机制及其作为干预靶点的可行性，特别是CHD/PAH肺组织BMP信号通路下调的新机制。

Researches confirmed that mutations in BMPRⅡ cause the genesis of pulmonary arterial hypertension, however, BMPRⅡmutations in congenital heart diseases associated pulmonary arterial hypertension(CHD/PAH) have the lowest frequency, so the underling mechanisms of the downregulation of BMP signal pathway in CHD/PAH require further investigation. Through an antibody microarray procedure, we found that, comparing with those of the normal age- and gender-matched subjects, the plasma levels of one of the BMP antagonists, NBL1, were significantly up-regulated in patients with CHD/PAH, furthermore, immunohistochemistry also confirmed that NBL1 demonstrated a conspicuous augmentation in the remodeled pulmonary arteries/arterioles in lungs from patients with CHD/PAH. Therefore, we proposed that NBL1 is possibly involved in the genesis and/or the progression of CHD/PAH. This study attempts to further investigate：① the alteration trend of the mRNA and protein level of NBL1 in lung tissues with the progression of PAH induced by systemic-to-pulmonary shunt，and the correlation between the plasma level of NBL1 and pulmonary hemodynamic index and the extent of pulmonary pathological lesions.; ② the effects of NBL1 on the proliferation，migration and apoptosis of human pulmonary arterial smooth muscle cells and endothelial cells, and the BMP signal pathway; ③the impact of blocking the endogenous NBL1 on the progression of PAH induced by systemic-to-pulmonary shunt. Conclusively, this study aims to investigate the mechanism of NBL1 involved in the remodeling process of pulmonary artery/arterioles and the potential of NBL1 to be a promising treatment target for CHD/PAH, especially, to provide an alternative elucidation for the BMP signaling reduction in lung tissues from CHD/PAH.