Innate immunity pathways and cellular metabolism signalling in pancreatic regeneration and carcinogenesis

胰腺癌是一种毁灭性的疾病，平均生存期约为6个月。胰腺癌发生的分子机制尚不清楚，细胞来源也不清楚。最近，在基因工程小鼠胰腺癌模型中显示，只有在伴随炎症存在的情况下，成年动物才能实现由内源性致癌Kras表达的恶性转化。在本提案的初步实验中，我们将危险和代谢信号相关的上皮细胞增殖定义为克服细胞内在的致癌信号屏障（即通过突变的Kras）的关键事件。在这方面，先天免疫TRIF/TBK1/IRF3/ 1型干扰素和代谢PPARgamma通路似乎在整合炎症和致癌信号中发挥重要作用。我们提出了一个新的概念，炎症诱导的这些通路的紊乱/失调为kras诱导的、不受控制的过度增殖和恶性转化奠定了基础。因此，在本研究中，我们旨在通过条件小鼠模型和原代分离细胞系统阐明这些通路在炎症损伤后胰腺再生和早期胰腺癌发生中的作用。

Pancreatic cancer is a devastating disease with a median survival of around 6 months. The molecular mechanisms of pancreatic carcinogenesis are poorly understood and the cell-oforigin is unknown. Recently, it has been shown in genetically engineered mouse models of pancreatic cancer that malignant transformation by endogenous expression of oncogenic Kras can only be achieved in adult animals if concomitant inflammation is present. In experiments preliminary to this proposal, we have defined danger and metabolic signalrelated epithelial proliferation as a key event for overcoming the cell-intrinsic barrier to oncogenic signalling (i.e. via mutated Kras). In this respect, the innate immunity TRIF/TBK1/IRF3/type 1 interferon and the metabolic PPARgamma pathway seem to play important roles in integrating inflammatory and oncogenic signals. We propose as a new concept that inflammation-induced disturbance/de-regulation of these pathways lays the basis for Kras-induced, uncontrolled hyperproliferation and malignant transformation. In this proposal, we thus aim at elucidating the role of these pathways in pancreatic regeneration following inflammatory injury and in early pancreatic carcinogenesis using conditional mouse models and primary, isolated cell systems.