DAN影响先天性心脏病所致肺动脉高压发展的机制研究

我们在前期研究中筛查了大量先心病肺高压患者的组织样本，首次发现DAN的浓度随肺高压进展而逐渐降低，继而应用体-肺分流型肺高压大鼠模型验证了上述发现。虽然DAN与肺高压密切相关，但现有结果无法判断DAN对肺高压具有促进还是抑制作用，其作用机制更是有待探索，因此结合文献提出研究假设：DAN通过拮抗BMP信号通路的增殖抑制作用促进体-肺分流型肺高压的发展。计划比较野生型大鼠和DAN基因敲除大鼠在构建体-肺分流型肺高压模型后8及12周时肺血管阻力、肺血管病理变化等指标，评价DAN是否对肺高压具有促进作用。在肺高压模型建立后，取一组DAN敲除大鼠补充DAN，并与不补充DAN的基因敲除大鼠进行比较，检测两组术后8及12周时BMP-2/4、BMPR1a/b、BMPR2、T-smad1/5/8、 P-smad1/5/8等指标的表达情况，评价DAN是否通过抑制BMP通路发挥作用，为进一步研发药物奠定基础。

In the preliminary study, it has been found that the expression of DAN (Differential screening selected gene Abberative in Neuroblastoma) protein is closely related to the degree of pulmonary artery hypertension (PAH) through screening of congenital heart disease patients. It was further verified in systemic-to-pulmonary artery shunt related PAH rat model study that DAN concentration was lower in rats with severer PAH. However, whether DAN would promote or suppress development of PAH remains unclear. According to former studies, we suppose that DAN expression would promote shunt-related PAH though preventing BMP (bone morpho-genetic proteins) signal pathway which leads to excessive proliferation of vascular smooth muscle cells. In the present study, pulmonary vascular resistance, pathological stage and artery intima-media thickness will be compared between wild rats and dan gene knockout rats at 8 and 12 weeks after they receive systemic-to-pulmonary artery shunt surgery, in order to evaluate the effect of DAN on shunt-related PAH development. Furthermore, the mechanism of DAN affecting shunt-related PAH development through BMP signal pathway will be explored by comparing BMP-2/4, BMPR1a/b, BMPR2, T-smad1/5/8, P-smad1/5/8 expression also at 8 and 12 weeks after shunt-related PAH models are established using dan gene knockout rats with and without supplement of recombinant DAN. The outcomes of the present study will provide important evidence of new intervention targets for shunt-related PAH intervention.