基于SREBP介导的脂质代谢重编程研究PI3K抑制剂PIK24抗呼吸道合胞病毒的作用机制

呼吸道合胞病毒（RSV）是导致幼儿急性下呼吸道感染最重要的病原体。临床尚无可用的主动预防疫苗和有效药物。RSV感染依赖于宿主，深入研究宿主因子参与病毒感染的分子机制，有助于挖掘新的抗病毒靶点和发现有效的抗病毒药物先导化合物。前期工作中，我们利用蛋白质组学研究方法发现RSV感染影响宿主细胞的脂质代谢，同时发现PI3K抑制剂PIK24具有显著的体内外抗RSV活性。作用机理表明，PIK24抑制PI3K信号通路且能调控SREBP的转录及其介导的脂质代谢。本项目拟利用分子、多种细胞和基因敲除小鼠模型结合基因沉默和过表达等技术深入阐明SREBP介导脂肪代谢重编程参与RSV感染的功能及分子机制，证实PI3K抑制剂治疗RSV感染的用途及作用位点；确证参与调节宿主脂肪代谢的病毒蛋白，为RSV感染性疾病防治提供有效治疗策略和先导化合物。

Respiratory syncytial virus (RSV) is the most important human pathogen causing acute lower respiratory tract infections which mainly affect children. There are no available vaccines or treatments in clinic. Virus life cycle achievement depends on host factors, thus the investigation on the pathogenetical mechanism and new therapeutic targets in RSV infection- related host factors is urgently needed. Based on the data of proteomics, we found that RSV infection affected the lipid metabolism of host cells, and PI3K inhibitor PIK24 had significant anti-RSV activity in vitro and in vivo. The mechanistic study demonstrated that PIK24 inhibited PI3K signaling pathway and regulated SREBP transcription and lipid metabolism. In the present project, we will focus on the following research contents: the role and the mechanism of SREBP-dependent lipidomic reprogramming in RSV infection, the new use and binding sites of PI3K inhibitor in treating RSV infection and the viral proteins involving in lipid metabolism of host cell. The project will provide the foundation for the understanding and development of PI3K inhibitors as novel anti-RSV agents.