重型急性胰腺炎（SAP）尚乏理想的药物治疗，其死亡率较高。胰腺内在的抗损伤和再生能力是影响急性胰腺炎（AP）预后的重要因素之一，但胰腺再生的分子机制远未阐明。本课题组前期发现在小鼠AP后损伤和修复模型中Reg4基因和蛋白表达呈先上升后下降的趋势，免疫荧光发现Reg4的表达主要分布在胰岛和胰岛周围残存的腺泡细胞及新生导管样上皮细胞中；使用重组Reg4蛋白减轻了AP的严重程度，而Reg4基因条件敲除加重胰腺损伤并明显抑制了胰腺再生，提示Reg4可能参与AP后胰腺抗损伤和再生过程。本研究拟利用基因敲除、RNAi技术研究Reg4对AP后腺泡细胞增殖、去分化及再分化的影响，以明确Reg4在胰腺再生过程中的作用，并通过高表达Reg4和应用外源性重组Reg4蛋白观察其对胰腺腺泡细胞EGFR和Notch信号通路的调节机制。本研究的完成将进一步阐明胰腺再生的分子机制并为胰腺功能障碍相关疾病治疗提供新的思路。

The mortality of severe acute pancreatitis (SAP) remains high, as lack of effective drugs to cure SAP. Pancreatic inherent ability to resist damage and self-repair is one of most important determinants influencing the prognosis of acute pancreatitis (AP). Our preliminary study showed that Reg4 expression was upregulated and then declined gradually down to normal during pancreatic injury and regeneration phase after acute pancreatitis. Expression of Reg4 was mainly localized in islet, residual acinar cells nearby islet and regenerating metaplastic epithelium. Recombinant human Reg4 (rReg4) protein ameliorated the mortality rate and the severity of experimental AP induced by both arginine and caerulein in vivo. In addition, rReg4 directly protected pancreatic acinar cells from necrosis induced by arginine in vitro. Furthermore, conditional knock out of Reg4 gene exacerbated pancreatic damage induced by caerulein and suppressed regeneration of exocrine pancreas after induction of AP. These results indicated that Reg4 probably participate in the regeneration of pancreas after acute pancreatic damage. In this study, the exact role of Reg4 in acinar cell proliferation, dedifferentiation and regeneration during experimental AP will be explored using gene-knock out technique and small interfering RNAs. Mechanism of Reg4 in regulating EGFR and Notch signaling will also be elucidated through overexpression of Reg4 gene and applying rReg4 protein. These results will probably help unravel the molecular pathogenesis of pancreatic regeneration and provide insight into the development of novel therapeutic agent for pancreatic diseases.