环状RNA-circ_0053503在儿童癫痫持续状态中的作用及机制研究

The status epilepticus (SE) is a big threaten to children’s health, thus uncovering the underlying mechanisms is urgent. Recent studies demonstrated that circRNA functions as the competitive endogenous RNA (ceRNA) by sponging the downstream miRNAs, Involving in the development of many nervous diseases. Our previous study revealed that circ_0053503 was highly overexpressed in the serum of SE children and model rats as well as the rat brain tissues. In addition, the levels of serum circ_0053503 was correlated with the clinical features of SE patients. Further investigation showed that circ_0053503 competitively bound to miRNA-223-3p, thus promoting the expression of NLRP3. In this proposal, we aim to apply the SE children cohort, SE rat model as well as the cell models to unveil the role of circ_0053503-miRNA-223-3p-NLRP3 axis in the onset and progression of SE. Moreover, we will also evaluate the predictive value of circ_0053503 in SE patient therapy and prognosis. Our results will bring new insights and strategies in effectively controlling SE.

儿童癫痫持续状态（Status Eepilepticuse, SE）的有效控制是儿科临床治疗的热点和难点，阐明其发生发展的分子机制至关重要。近年研究表明，环状RNA（Circular RNA, circRNA）作为竞争性内源RNA可“吸附”下游微小RNA（miRNA），参与多种神经系统疾病的发生发展。我们前期研究发现，hsa_circ_0053503在SE大鼠模型脑组织及SE患儿血浆中均表达上调，且表达水平与SE患儿临床特征显著相关；进一步研究发现hsa_circ_0053503可竞争性结合miRNA-223-3p，进而调控下游靶基因NLRP3的表达，促进SE进程。本课题拟利用SE患儿人群队列、SE大鼠及细胞模型，系统地探索hsa_0053503-miR-223-3p-NLRP3信号轴在SE发生发展中的确切分子机制及潜在的精准医学价值，并为今后SE的治疗及预后判断提供重要理论依据和参考。

本研究通过分析健康对照儿童及SE患儿血浆circRNA表达谱，筛选出在SE患儿血浆中表达显著升高的环状RNA-circ_0053503，进一步在SE大鼠模型的脑组织中得到了验证该结果；临床相关分析提示circ_0053503的表达水平与SE患儿的抽搐时间密切相关，circ_0053503表达量越高的患儿，抽搐时间越长；进一步我们通过一系列分子生物学实验，证实了circ_0053503可以通过竞争性结合miR-223-3p，间接调控miR-223-3p下游靶基因NLRP3的表达，引发下游的炎症瀑布，从而参与SE的发生发展。同时我们发现SE治疗敏感组组患儿的炎症因子IL-18、IL-1β表达明显低于治疗耐药组，进一步佐证了炎症反应在SE中的作用。后续我们通过已经建立的SE随访患儿队列，系统评价circ_0053503及其下游靶基因调控信号轴在SE患儿疗效和预后中的临床价值，发现SE治疗敏感组和治疗耐药组相比，circ_0053503的表达量明显降低，而miR-223-3p的表达在各组间无明显差异，提示circ_0053503可能作为评价预后的指标之一。综上所述，我们揭示了circ_0053503发挥ceRNA的“吸附”作用，竞争性结合miR-223-3p，调控NLRP3的表达，促进了SE的发生发展的新机制，为今后筛选SE潜在的治疗靶点和预后判断提供重要的科学依据。