核内输蛋白（importin）通过介导基因组风暴促进暴发性心肌炎发生发展的机制及干预研究

暴发性心肌炎通常指病毒感染导致的严重心脏损害，死亡率高达50%。目前认为炎症风暴是其发生基础，但机制仍不明确。基因组风暴（genomic storm）是炎症风暴源头事件，而核内输蛋白（importin）介导应激反应转录因子（SRTFs）入核并激活大量炎症相关靶基因转录，是基因组风暴始动环节。我们发现，核内输蛋白抑制剂可改善暴发性心肌炎小鼠生存率、心功能及炎症浸润、减少病毒复制。生物信息学显示核内输蛋白也是SRTFs靶点，提示存在SRTFs-imp正反馈环路，放大基因组风暴效应。因此本课题拟从临床样本、动物及细胞模型等层面，论证科学问题：①暴发性心肌炎存在基因组风暴；②核内输蛋白是否通过介导SRTFs入核、影响病毒复制、SRTFs-imp正反馈环路等机制参与促进暴发性心肌炎；③核内输蛋白抑制剂能否治疗暴发性心肌炎。本研究将加深暴发性心肌炎理论认识，为这类以炎症风暴为核心的疾病提供新治疗思路。

Fulminant myocarditis is a severe cardiac inflammatory disorder which is usually caused by viral infection, with a high in-hospital mortality of approximate 50%. It is recognized that inflammatory storm is the key pathophysiological process for fulminant myocarditis, but the detailed mechanisms are not well demonstrated yet. The inflammatory storm is activated by an initiating event called genomic storm, which is characterized by massive transcription of inflammation-related genes, due to importin-mediated active nuclear translocation of stress-responsive transcription factors (SRTFs). Recently, we found that importin inhibitor showed protective effects on a mouse model of fulminant myocarditis, improving the survival, cardiac functions and inflammatory infiltration, as well as reducing the viral titer in hearts. Then a bioinformatic analysis showed that importin is also a potential target of SRTFs, suggesting the existence of a SRTFs-imp positive feedback loop which amplified the size of genomic storm. So, we will use clinical samples, animal and cellular models of fulminant myocarditis as objects, to investigate the following hypotheses: ①Genomic storm is involved in the process of fulminant myocarditis; ②Whether importin promotes the progression of fulminant myocarditis via mechanisms like mediating the nuclear translocation of SRTFs, influencing the viral replication and participating in the SRTFs-imp positive feedback loop; ③Whether the importin inhibitor works in the treatment of fulminant myocarditis. By studying this program, we will make better understanding of the pathophysiological basis of fulminant myocarditis, and it will also provide a novel therapeutic target for those diseases with predominant inflammatory storm.