成纤维细胞生长因子21（FGF21）抑制高脂饮食相关胰腺炎症的作用机制研究

Acute and chronic pancreatitis is series of diseases caused by uncontrolled trypsin activation and persistent inflammation. Cationic trypsinogen (PRSS1) gene mutation is commonly seen in pancreatitis patients. Numerous clinical studies have provided evidence of the connection between obesity and pancreatitis. Fibroblast Growth Factor 21 (FGF21) has recently been found to play a major role in lipid and glucose metabolism. Instead of the liver, FGF21 has been found to have the highest expression level in pancreas tissue in recent studies. In addition, FGF21 has been proven to have protective effect against cerulein induced pancreatitis. We designed this study using a new animal model carrying PRSS1 mutation in combination with High Fat Diet treatment. Furthermore, we examine the protective effect of FGF21 in this animal model and whether it functions by inducing the expression of PGC1α to increase mitochondria oxidative phosphorylation. This study will be a solid evidence of the application of FGF21 on pancreatitis patients.

胰腺炎是胰酶激活引起胰腺自身消化而导致的急慢性炎症，但具体发病机制未明。近期研究发现肥胖相关通路可能参与胰腺炎的发病过程，FGF21(fibroblast growth factor 21)是调节脂代谢的关键酶之一。我们前期研究发现，FGF21在胰腺中表达水平极高，且可减轻化学因素诱导的胰腺炎症。PGC1α与FGF21的表达水平显著正相关，且可参与胰腺腺泡细胞线粒体氧化磷酸化水平调节。由此提出假说：FGF21通过靶向调节PGC1α表达水平，提高胰腺腺泡细胞线粒体氧化磷酸化水平，减轻炎症发生中的脂毒性。本课题拟利用PRSS1基因突变的R122H/Cre转基因小鼠，建立高脂饮食诱导的急慢性胰腺炎模型，探讨FGF21/PGC1α通路在肥胖加重胰腺炎严重程度中的具体机制。为减轻胰腺炎死亡率、改善预后提供新的治疗靶标。

由各种内外因素引起的腺泡细胞损伤从而激活胰腺的损伤修复系统。但若造成损伤的内外因素持续存在，就会导致修复系统的过度激活和失控，最终导致胰腺的加重或持续性炎症反应，甚至器官纤维化和功能衰竭。本研究中，我们明确了临床患者血清FGF21与胰腺炎的关系；建立了稳定的急慢性胰腺炎动物模型以及相关药物治疗和药物筛选模型；明确R122H基因突变小鼠在高脂饮食处理下的胰腺病变程度以及FGF21对改模型小鼠胰腺炎的治疗作用，并通过多种体外实验探索FGF21对腺泡细胞、胰腺星状细胞和巨噬细胞等的保护作用和分子机制，以及在胰腺星状细胞和腺泡细胞中影响FGF21表达调控的分子机制。接下来将进一步探讨利用FGF21治疗临床急慢性胰腺炎的可能性和具体方法策略，为减轻胰腺炎死亡率、改善预后提供新的治疗手段。