感染等诱发中性粒细胞胞外捕网(NETs)形成释放自身抗原，是中性粒细胞胞浆抗体相关性血管炎(AAV)的关键。根据自噬可调节凋亡、NETs转换的特性，及转录因子Sox作为细菌DNA传感器致mTOR表观遗传学修饰引发自噬的最新进展，结合AAV患者NETs增加及NETs形成依赖自噬的前期发现，推测感染时Sox2通过识别细菌DNA，募集NuRD复合物，抑制mTOR启动子活性，增强自噬诱导NETs形成。拟进一步通过临床分析，联合前期FimH融合蛋白成功诱导大鼠血管炎模型的基础上，通过含全基因组DNA大肠杆菌再感染，联合组蛋白去乙酰化酶（HDAC1）抑制剂及自噬阻断剂，通过液相芯片、免疫印迹、ChIP、DNA甲基化、组蛋白修饰等方法，认识Sox2-NuRD-mTOR-自噬途径对NETs的作用及调控机制，以期从表观遗传学角度，一定程度实现中性粒细胞程序性死亡的“重编程”，诱导免疫耐受，寻求治疗新靶点。

Neutrophil extracellular traps (NETs) formation induced by bacterial infection contributes to the key role in pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Our previous data had shown that autophagy is involved in ANCA-induced NET formation in human neutrophils. New evidence indicates that transcription factor Sox2 as a cytosolic sequence-specific DNA sensor in neutrophils directly recognized microbial DNA through its high-mobility-group domain. Sox2 binds to a repressive region on the mTOR promoter and recruits the NuRD complex to mediate transcriptional repression. The NuRD complex epigenetically regulates the mTOR promoter temporal regulation of autophagy as a key step in cellular reprogramming processes. Based previous data that apoptosis might function as a backup program for NETosis when autophagy is prevented, we therefore hypothesize that the interplay between autophagy, dependent pathway promotes the collapse of both nuclear and granular membranes and mediates intracellular chromatin decondensation, while inhibiting the NETs machinery hopefully elucidate in detail the interplay between these processes and the essential enzymatic activities involved. Accordingly, the overall aim of this research project will be to determine that if bacterial DNA triggers Sox2-depended nucleosome remodeling and deacetylase (NuRD) complex-induced mTOR mediate autopahgy play key role in NETs formation. In order to fully study this aim, the abnormal death mode of neutrophils will be investigated based our preliminary experiment results in AAV pateients. Using immunized WKY rats model with purified FimH fusion protein emulsified in Titermax Gold, further combined specific inhibitor for histone deacetylase (HDAC1) and autophagy, or inhibition of mammalian target of rapamycin (mTOR) induce autophagy in vivo. The proteins of Sox2, NuRD complex (Mi-2b, LSD1, MTA2 and HDAC1) and mTOR will be tested by liquid chip, immunoblotting and Chromatin Immunoprecipitation (ChIP) assay. The DNA methylation and histone modification will be investigated by commercial kits. Findings from this study may eventually lead to the development of safe and rational therapy to ameliorate vasculitis and abrogate the autoimmunity in individuals suffering from AAV.