自身动力性Fontan循环通过LEENE抑制miR-503-5p调控PI3K/AKT/eNOS通路保护肺血管内皮功能的机制研究

功能性单心室是一类复杂的先天性心脏病，目前唯一的治疗方案是Fontan手术，但术后远期并发症发生率高，其根本原因在于缺乏右心室搏动作用。申请人前期设计了自身动力性Fontan循环，利用计算流体力学方法验证了该循环可提升血流动力，并提供搏动性血流；大动物实验同样提示该循环能维持肺血管内皮eNOS表达，从而保护血管内皮功能。进一步的测序结果发现搏动性血流可能通过LEENE的海绵吸附效应抑制miR-503-5p，进而激活PI3K/AKT通路。据此假设：自身动力性Fontan循环为肺循环提供搏动性血流，并通过LEENE抑制miR-503-5p，激活PI3K/AKT通路，促进eNOS的合成，保护肺血管内皮功能。本研究拟在细胞水平探索LEENE与miR-503-5p的相互作用，以及对PI3K/AKT/eNOS的调控机制，并动物模型上验证该假说，为优化Fontan手术和改良预后提供理论基础和应用前景。

Functional single ventricle is a class of congenital heart disease, and the only treatment option available is the Fontan procedure, but the cause of the high rate of long-term complications is the lack of right ventricular pulsatile blood. We has designed an self-powered Fontan circulation, which was demonstrated to provice hemodynamic and pulsatile flow. Further high-throughput sequencing results revealed that pulsatile blood flow may inhibit miR-503-5p through the sponge effect of LEENE, which in turn activates the PI3K/AKT pathway. It is hypothesized that the self-powered Fontan circulation provides pulsatile blood flow to the pulmonary circulation and activates the PI3K/AKT pathway through the inhibition of miR-503-5p by LEENE, which promotes the synthesis of eNOS and protects pulmonary vascular endothelial function. This study intends to explore the interaction between LEENE and miR-503-5p at the cellular level and the regulatory mechanism of downstream PI3K/AKT/eNOS, and test the hypothesis on animal models. This study provide a theoretical basis and application prospects for optimizing Fontan procedure and improving prognosis.