KLHL21基因罕见变异靶向调控NF-κB信号通路促进心肌梗死的分子机制研究

心肌梗死是一种多因素疾病，其发病机制尚未完全阐明。其家族聚集发病提示心梗和遗传密切相关。我们在一个完整心梗家系中通过外显子组测序，鉴定出KLHL21基因罕见的错义变异位点(Arg588Trp)，呈常染色体显性遗传并和家系患病成员呈现表型共分离现象，提示该突变是该家系心梗的致病基因，但其具体机制不清。文献表明，KLHL21基因可直接结合IKK，负向调控NF-κB信号通路。课题组前期通过构建心梗小鼠模型发现梗死区NF-κB信号通路持续激活；通过构建KLHL21和ApoE双基因敲除小鼠模型发现主动脉不稳定斑块负荷明显增加并易破裂。因此我们推测KLHL21基因错义突变所致KLHL21蛋白功能异常，影响其与特异性底物的结合，从而激活了NF-κB信号通路，促进了心梗的发生。为验证该假说，本项目拟通过细胞水平以及构建基因敲除/敲入小鼠模型进行整体功能研究，以揭示罕见变异在心梗发病机制中的作用。

Myocardial infarction is a multifactorial disease, and its pathogenesis has not been fully elucidated.The familial cluster suggests that myocardial infarction is closely related to heredity.We identified a rare missense mutation locus (Arg588trp) of KLHL21 gene in a complete myocardial infarction family by exome sequencing, which was inherited in an autosomal dominant manner and co-isolated phenotypically from the disaffected members of the family, suggesting that this mutation is the pathogenic gene of myocardial infarction in this family,but its specific mechanism is unclear. Study has shown that KLHL21 can directly bind to IKK and negatively regulate NF-κB signaling pathway.The NF-κB signaling pathway was continuously activated in the infarct area through the establishment of a mouse model of MI.The KLHL21 and ApoE knockout mouse models showed that the aortic unstable plaque load increased significantly and was prone to rupture. Therefore, we speculate that KLHL21 protein function abnormalities caused by missense mutation of KLHL21 affect the binding of KLHL21 with specific substrates, thus activating NF-κB signaling pathway and promoting the occurrence of myocardial infarction.To verify this hypothesis, this project intends to study the overall function of KLHL21 gene by mouse models and functional experiments at the cellular level, to reveal the role of rare variants in the pathogenesis of myocardial infarction.