MFG-E8/ABCE1/ATG16L1信号轴调控腺泡细胞自噬促进重症急性胰腺炎损伤修复的作用及机制研究

重症急性胰腺炎（SAP）是常见的消化系统危重症。有研究显示胰腺腺泡细胞内自噬流紊乱与SAP发病密切相关，但具体机制仍不明确。我们前期研究发现，乳脂球表皮生长因子8（MFG-E8）基因敲除可加剧小鼠发生SAP后腺泡细胞损伤及细胞内自噬流紊乱的程度，表明MFG-E8可能是调节自噬及腺泡细胞损伤的关键因子；同时，数据库筛查和免疫共沉淀实验提示MFG-E8可与自噬调控分子ABCE1特异性结合，后者通过影响ATG16L1的表达调节细胞内自噬流的稳态。据此我们提出假设：腺泡细胞内MFG-E8通过与ABCE1结合，参与调控ATG16L1的表达进而维持细胞内自噬流稳态，最终促进SAP损伤的修复。我们将通过构建胰腺特异性MFG-E8过表达+ABCE1敲除双重基因修饰小鼠，并结合体外实验，探索腺泡细胞内MFG-E8对SAP细胞自噬和损伤的作用及机制。本项目有望进一步阐明SAP的发病机制，为临床干预提供靶点。

Severe acute pancreatitis (SAP) is a common critical disease of the digestive system. Studies have shown that the disorder of autophagy flux in pancreatic acinus cells is closely related to the incidence of SAP, but the specific mechanism is still unclear. Milk fat globule epidermal growth factor 8 (MFG-E8) is a lipophilic glycoprotein. Our previous work has shown that MFG-E8 gene knockout which exacerbated acinar cell injury and intracellular autophagy flux disturbance after SAP induction in mice. It is suggesting that MFG-E8 could be a key factor in regulating autophagy and acinar cell injury. Simultaneously, both database screening and immunoprecipitation confirmed that MFG-E8 could bind to ABCE1 in particular. As an essential regulator of autophagy, ABCE1 regulates autophagy homeostasis by influencing the expression of ATG16L1. Based on the above evidence, we assumed that MFG-E8 in acinar cells can affect ATG16L1 expression by specific ABCE1 binding and then facilitating the recovery of autophagy flux, and participate in the repair of SAP injury. The effect and mechanism of MFG-E8 in acinar cells on autophagy and injury in SAP will be explored by constructing pancreas-specific mfge8 overexpression+abce1 knockout dual gene modified mice. The aim of this study is to explain the pathogenesis of SAP and to provide a theoretical basis for therapeutic intervention.