胰腺应激蛋白PSP/reg 抑制T2DM胰岛纤维化和胰腺癌发生的细胞分子机制

Our current ongoing research funded by National Natural Science Fund for Youth has found that PSP/reg was significantly increased in chronic pancreatitis. It may act through inhibiting the activation of PSC, a central player for developing pancreatic fibrosis, subsequently reverses the pancreatic fibrosis and enhances the pancreatic regeneration after injury; therefore it may play a role in pancreatic natural protective process. Recent studies suggest that islet fibrosis is the key step to the development of type 2 DM (T2DM), and it is well known PSP/reg is a growth factor for islet beta cell regeneration. Whether or not it is through inhibiting PSC activation for PSP/reg to reduce islet fibrosis and in turn improve islet beta cell function remains to be investigated. T2DM is a risk factor for the development of pancreatic carcinoma. Under the influence of hyperglycemia and hyperinsulinemia, PSC activation is the initiating and key step for developing islet and pancreatic fibrosis and may play an important role in the pathogenesis and progression of pancreatic carcinoma, while the underlying mechanisms remain to be explored. Based on our discovery from our ongoing funded project, by using PSP/reg and clinical available T2DM treatment medications, Our current application is to focus on the morphological characteristics of the islet, beta cell function, PSC activation and the genesis and resolution of fibrosis, to compare PSP/reg levels in patients with pancreatic cancer and corresponding clinical stages of T2DM; to further investigate the effect and potential molecular mechanisms of PSP/reg on islet fibrosis and pancreatic fibrosis in patient with T2DM, and eventually to provide new treatment targets for T2DM and pancreatic cancer.

青年基金项目发现胰腺分泌应激蛋白PSP/reg在慢性胰腺炎时显著升高，可能通过抑制胰腺星状细胞 (PSC) 活化，推动胰腺纤维化逆转，促进组织再生修复，从而发挥胰腺的自身保护作用。近年来研究表明，2型糖尿病 (T2DM) 重要环节是胰岛纤维化，PSP/reg是公认的胰岛β细胞再生因子，PSP/reg是否通过抑制胰岛PSC活化减轻胰岛纤维化从而改善胰岛β 细胞功能，值得进一步探讨。T2DM是胰腺癌发生的危险因素，高糖高胰岛素环境下PSC 活化是胰岛和胰腺纤维化发生的始动和关键环节，可能参与了T2DM与胰腺癌的发生发展。本课题拟利用基因重组的PSP/reg 和药物干预，比较胰岛形态结构、β 细胞功能、PSC活性及胰腺纤维化的演变，检测不同病程T2DM与发生胰腺癌患者血清PSP/reg 水平，探讨PSP/reg对T2DM胰岛和胰腺纤维化的影响及细胞分子机制，为治疗T2DM和防治胰腺癌提供新思路。

2型糖尿病（Type 2 diabetes mellitus, T2DM)是一种具有胰岛素抵抗及β细胞功能受损的疾病，主要与β细胞凋亡加速有关。胰腺损伤时，胰腺分泌胰石蛋白/再生蛋白 (pancreatic stone protein / regenerating protein, PSP/reg) 水平显著升高。研究显示，PSP/reg是胰岛β细胞的生长因子，提示其对防控糖尿病具有重要的临床价值。本课题组最近与瑞士的合作研究发现，初发T2DM组、糖尿病慢性并发症组的血清PSP/reg水平显著高于正常对照组。PSP/reg水平升高越多，越易合并糖尿病慢性并发症(血管、神经病变)，提示血清PSP/reg升高可能成为糖尿病合并慢性并发症的新预测因子。. 目前越来越多的证据显示，T2DM增加胰腺癌发生风险，可能与高血糖、高胰岛素血症、胰岛素样生长因子（insulin like growth factor，IGF）、免疫功能调节紊乱及氧化应激等有关。本研究发现，PSC 表面存在高表达的胰岛素受体和IGF-1受体（insulin and IGF-1 receptor, IR/IGF-1R），且胰岛素显著促进PSC 的活化、增殖、细胞外基质合成及半乳凝素-3(Gal-3)表达。因此，T2DM高糖、高胰岛素环境下PSC活化是胰腺纤维化发生的始动和关键环节，可能参与了胰腺癌发生过程。新近研究发现，二甲双胍可快速改善胰岛素抵抗IR，降低血中胰岛素水平，并明显降低胰岛和腺管细胞的增生，从而防止胰腺癌的发生。本课题组研究进一步证实，二甲双胍抑制PSC活化、增殖、迁移，并激活AMPK信号通路，可能为治疗T2DM和防治胰腺癌提供新思路。. 课题成果参加美国胰腺年会、美国消化疾病周、美国糖尿病年会和欧洲糖尿病年会大会交流，并在SCI收录杂志Endocrine和Am J Physiol及国内核心杂志上发表文章。课题组与德国、瑞士、美国等国际一流大学合作，进一步拓展逆转胰腺纤维化的相关研究。研究成果将为防治胰腺炎、胰腺癌纤维化，以及糖尿病胰岛纤维化提供新靶点，开拓新思路，具有潜在的社会和经济效益。