Ghrelin通过GHSR1a-EGFR-ERK途径调控胰腺Lgr5+细胞分化参与急性胰腺炎后腺泡细胞再生的机制研究

急性胰腺炎（AP）后胰腺坏死修复不佳可导致病程延长，后期外分泌功能不全发生增加。LGR5+细胞在胰腺损伤后显著增加，并在体外可培养成具有多能干细胞特性的胰腺类器官。我们发现Ghrelin在胰腺类器官中可促进LGR5和腺泡细胞标记物Amy2表达增加。在AP患者和小鼠模型中，血清Ghrelin浓度在修复期显著增加。而Ghrelin在十二指肠溃疡等多种损伤模型中可通过GHSR1a-EGFR-ERK途径促进组织损伤修复，其受体GHSR-1a在胰腺类器官中与LGR5共表达。因此我们假设Ghrelin可能通过GHSR1a-EGFR-ERK途径调控LGR5+细胞分化参与AP后腺泡细胞再生，并使用3D胰腺类器官及AP动物模型，通过流式细胞、免疫荧光、Rt-PCR、Western-blot 、EDU-click-it方法等技术，验证上述假设，探索AP后胰腺损伤修复的新机制和治疗新靶点。

Incomplete pancreatic repair after acute pancreatitis (AP) may prolong the AP course and increase the incidence of exocrine pancreatic insufficiency after AP.LGR5+ cells increased dramatically after pancreatic injury and can be cultured into pancreatic organoid with multipotent stem cell characterization . We found that ghrelin can promote the expression of LGR5 and Amy2 (acinar cell marker) in pancreatic organoid. Besides, the concentration of serum ghrelin increased in repair phase in AP patients and AP mice model. Ghrelin can promote the repair progress by GHSR1a-EGFR-ERK pathway in many injury repair model including duodenal ulcer, which was co-expressed with LGR5 in pancreatic organoid. Therefore, we hypothesized Ghrelin regulates differentiation of pancreatic LGR5+ cell by activating GHSR1a-EGFR-ERK pathway to promote acinar cell regeneration after Acute pancreatitis. We will use 3D cultures of pancreatic organoid, AP mice model, flow cytometry, immunofluorescence, Rt-PCR, Western-blot, EDU-click-it and etc.to explore the hypothesis and the mechanism of pancreatic injury repair after AP and provide useful target for the treatment of AP.