miR-146b-5p/TRAF6/ULK1轴调控腺泡细胞缺陷性自噬在急性胰腺炎发病中的作用及其机制

The pathogenesis of acute pancreatitis (AP) is so sophisticated to be elucidated and there is no specific management has been developed to cure AP. The presence and its alterations of impaired autophagy within pancreatic acinar cells could regulate the severity of AP-related injuries via some mechanisms that are still to be well acknowledged. In our preliminary experiments, we found pancreatic level of tumor necrosis factor receptor-associated factor 6 (TRAF6) was up-regulated after AP induction. In addition, pancreatic level of TRAF6 correlated well with activation of autophagy-related protein ULK1, accumulation of cytoplasmic autophagic vacuoles and pancreatic histopathological and subcellular structural injuries. MiR-146b-5p was figured out as an upstream miR that specifically regulated the activity of TRAF6. Taking the interactions and corresponding regulations among miR-146b-5p/TRAF6/ULK1 axis as a key interest, the present study is established to discuss regulations and its potential mechanism of impaired autophagy via miR-146b-5p/TRAF6/ULK1 axis within pancreatic acinar cells after AP induction. Furthermore, whether or not miR-146b-5p/TRAF6/ULK1 axis could regulate AP-related injuries via its regulation upon impaired autophagy within pancreatic acinar cells will be tested. Our findings might shed a new light on the future fundamental and clinical AP-related researches.

急性胰腺炎（AP）发病机制至今尚未阐明，其临床诊治尚无特异性手段。胰腺腺泡细胞缺陷性自噬的存在及其调控可显著影响AP相关性损伤的严重程度，但其机制尚缺乏全面、统一的认知。前期工作中，我们发现肿瘤坏死因子受体相关因子6（TRAF6）的表达在大鼠AP胰腺组织中显著上调，且其浓度与胰腺组织内自噬相关蛋白ULK1的活化、自噬性空泡的堆积、胰腺组织病理学及亚细胞结构损伤程度均呈正相关；而TRAF6的基因表达又接受上游miR-146b-5p的特异性调控。本研究旨在以miR-146b-5p、TRAF6及ULK1三者之间的相互结合及其效应为核心，探讨miR-146b-5p/TRAF6/ULK1轴对AP胰腺腺泡细胞缺陷性自噬的调控及其机制，并验证miR-146b-5p/TRAF6/ULK1轴通过调控腺泡细胞缺陷性自噬从而影响AP相关性损伤的功能，以期为今后AP相关的基础与临床研究提供新的思路及实验依据。

急性胰腺炎（AP）发病机制复杂，至今尚未阐明，其临床诊治尚无特异性手段。胰腺腺泡细胞内酶原的异常激活是AP致病的始动事件，但其发生机制尚缺乏全面、统一的认知。本研究中，我们发现肿瘤坏死因子受体相关因子6（TRAF6）的表达在大鼠AP胰腺组织中显著上调，且与胰腺局部及系统性炎性损伤程度呈正相关。在此基础之上，我们发现胰腺腺泡细胞内TRAF6的表达受上游miR-146b-5p的负性调控，而其下游则又通过直接结合并调控溶酶体内组织蛋白酶B（CAT B）的成熟进而调控酶原的活化。本研究结果提示miR-146b-5p/TRAF6/CAT B轴通过调控腺泡细胞胰腺酶原的活化进而影响AP的炎性损伤，这一新颖通路的发现及其潜在机制的阐明有望为今后AP的临床诊治提供新的思路及着力点。