肿瘤坏死因子受体相关因子6对高甘油三酯性胰腺炎细胞焦亡的影响与机制研究

高甘油三酯性胰腺炎（HTGP）易重症化，游离脂肪酸（FFA）对胰腺组织的损伤是HTGP发病的基础环节，其机制可能与FFA激活细胞焦亡（pyroptosis）导致炎症级联反应有关。已经证实，细胞焦亡的激活受Toll样受体（TLRs）、炎症小体NLRP3调控，而肿瘤坏死因子受体相关因子6（TRAF6）是此通路关键蛋白。本课题前期研究发现HTGP大鼠胰腺病理损害加重，胰腺腺泡细胞AR42J受脂多糖刺激后TLR9表达上调、促炎细胞因子释放增多。由此推测细胞焦亡可能是HTGP重症化的关键环节，调控TRAF6的表达可能通过TLR9/NLRP3信号通路影响腺泡细胞焦亡及炎症反应。本项目拟通过细胞实验探讨①不同TG水平对AR42J细胞焦亡的影响；②调控TRAF6基因表达对细胞焦亡的影响，其机制与TLR9/NLRP3通路的关系；继而在HTGP动物实验探讨③TRAF6抑制剂是否可以改善HTGP胰腺损伤。

Acute pancreatitis (AP) is one of the common emergency disease. The incidence rate of hypertriglyceridemia-associated pancreatitis (HTGP) increases year by year and has become the third leading cause of AP in China. HTGP is easier to have a severe course than the acute pancreatitis (AP) patients causing by other causes. However, the molecular mechanisms of HTGP are remain unclear. It was found that the damage of free fatty acid (FFA) to the pancreatic tissue is the initial step of the pathogenesis of HTGP, and its mechanism may be related to the inflammatory cascade reaction caused by FFA activation of pyroptosis. Pyroptosis，a highly inflammatory form of programmed cell death that occurs most frequently upon infection with intracellular pathogens, which is associated with many infectious diseases. It has been demonstrated that the expansion of inflammation caused by pyroptosis is related to the multiple organ dysfunction syndrome (MODS) induced by server acute pancreatitis (SAP). When the pyroptosis induced by HTGP is controlled, it is expected to reduce the damage of pancreatic and improve the prognosis. Previous studies on the molecular mechanism of pyroptosis have shown that toll-like receptor (TLRs) and inflammatory corpuscles NLRP3 involves the activation of pyroptosis, and the tumor necrosis factor receptor-associated factor 6 (TRAF6) is play a role in this pathway. Previous studies from our lab also found that the pathological damage of the pancreas of HTGP rats was aggravated. The expression of TLR9 in the pancreatic acinar cell AR42J was up-regulated and the release of pro-inflammatory cytokines was increased after the stimulation of LPS. Therefore, we hypothesize that pyroptosis is supposed to be an important mediator in the intensification of HTGP, and the regulation of TRAF6 expression may affect the pyroptosis and inflammatory response of acinar cells through the TLR9/NLRP3 signaling pathway. This project intends to: ①To explore the effects of different TG levels on the pyroptosis of AR42J cells;②To investigate the effects of TRAF6 gene expression on pyroptosis and the relationship between it and TLR9/NLRP3 pathway. ③To Establish the HTGP rat model and Observe whether the TRAF6 inhibitor can improve the pancreatic damage and inflammatory reaction of HTGP.