C/EBPβ通过Atg4及/或DAPK1诱导异常自噬在高甘油三酯血症性急性胰腺炎发病中的机制研究

高甘油三酯血症性急性胰腺炎（hypertriglyceridemic pancreatitis, HTGP）发病率逐年升高，病情危重，但其发病机制仍不清晰。胰腺腺泡细胞内的胰蛋白酶原加速激活是介导HTGP胰腺损伤的首要步骤之一，自噬异常参与酶原激活的关键过程。我们前期研究发现：HTGP中核转录因子C/EBPβ表达增多，及存在异常自噬流。有研究报道C/EBPβ可以调控自噬，因此，本项目拟通过制备HTGP动物模型和分离培养胰腺腺泡细胞，阐明C/EBPβ通过调控以下途径：即自噬相关基因Atg4b和/或C/EBPβ与激活转录因子6（ATF6）结合后再激活死亡相关蛋白激酶1（DAPK1），诱发胰腺异常自噬，引起胰腺腺泡细胞内酶原加速激活，从而参与胰腺炎病情进展，以期能为针对性治疗HTGP提供科学的理论依据。

The incidence of hypertriglyceridemic acute pancreatitis is increasing but the specific pathogenesis remains poorly understood. Inappropriate activation of trypsinogen to trypsin within pancreatic acinar cells is a key factor leading to the development of pancreatitis. Impaired autophagy is involved in trypsinogen activation. In our previous study, we found expression of nuclear transcription factors C/EBPβ was upregulated and impaired autophagy in HTGP. It was reported that autophagy is regulated by C/EBPβ in several studies. Using animal model and in vitro cell model, We aim to confirm that C/EBPβ regulates impaired autophagy in HTGP and have influence on pancreatitis development and study the mechanisms through the follow signal pathway:(ⅰ)C/EBPβ activating autophagy related gene Atg4b pathway;(ⅱ)C/EBPβ integrating with ATF6 then to activate DAPK1 pathway. We hope the results of our study about targeting C/EBPβ/autophagy pathway will provide a theoretical basis in therapy of HTGP.