LINC01312调控TCF21表达在川崎病冠状动脉损伤中的分子机制研究

川崎病冠状动脉病变（CAL）是决定患儿远期预后的重要因素，病因与发病机制不明。课题组通过全基因组关联研究发现，非编码RNA基因LINC01312 rs1208285多态性与川崎病CAL发生相关。表达数量性状基因座分析提示该位点可调控转录因子21（TCF21）表达。文献报道TCF21可调控TNF-α和IL-6等炎症因子的释放，因此推测LINC01312调控TCF21表达参与川崎病CAL的发生。本课题拟：在另一组独立人群中验证该位点与CAL的相关性；在人单核细胞和人冠状动脉内皮细胞共培养模型中，研究LINC01312多态性调控TCF21表达对内皮功能的影响，并通过ChIP-seq和RNA-seq确定其调控的下游信号通路和炎症因子；CRISPR/Cas9构建点突变小鼠，观察小鼠炎症反应和冠状动脉病变。本课题有助于从lncRNA角度理解川崎病CAL发生机制，为临床早期预测和治疗CAL提供理论依据。

Coronary artery lesion (CAL) caused by Kawasaki disease is an important factor in determining children’s long-term prognosis. The etiology and pathogenesis remain unclear. Through a genome-wide association study, we found that the non-coding RNA gene LINC01312 rs1208285 polymorphism was associated with CAL in Kawasaki disease patients. Expression quantitative trait loci analysis indicats that rs1208285 can regulate the expression of transcription factor 21 (TCF21), which is reported to have an association with the release of inflammatory factors such as TNF-α and IL-6. We speculate that LINC01312 regulates TCF21 expression and therefore plays a role in the occurrence of CAL. In this study, we intend to verify the association between LINC01312 rs1208285 and CAL in an independent group of patients with Kawasaki disease; investigate the regulatory mechanism of LINC01312 polymorphism on TCF21 expression and on endothelial function in co-cultured human monocytes and human coronary endothelial cells; determine the downstream signaling pathways and inflammatory factors regulated by TCF21 through ChIP-seq and RNA-seq; construct point-mutant mice by CRISPR/Cas9 and study the effects of rs1208285 on inflammation and coronary arteries. This study helps to understand the mechanism of CAL in Kawasaki disease from a perspective of lncRNA, and provides theoretical basis for its early predictation and managment of CAL.