Characterization of a Tlr3-Trif-dependent progenitor cell status duringpancreatic regeneration and pancreatic carcinogenesis.

炎症微环境在肿瘤的发生和发展中起着重要作用，并在胰腺癌的发生中得到了充分的证明。尽管toll样受体（Tlr）信号通路在协调免疫细胞早期病原体检测的先天免疫中的作用备受争议，但在非免疫细胞中激活Tlr3信号通路的目的仍然难以捉摸。Tlr3信号通过识别病原体或损伤相关的分子模式（分别为PAMPs或DAMPs）如双链RNA诱导，并通过激活下游途径成分Irf3和Irf7促进I型干扰素应答。先前的数据表明，全球Tlr3和Triflps2敲除小鼠在cerulein介导的胰腺炎后显示外分泌细胞损伤增加，而I型干扰素处理胰腺上皮细胞外植体可以加速祖基因的重新表达。在这方面，我们假设胰腺上皮细胞的内在Tlr3信号可能影响胰腺再生过程中腺泡细胞向祖细胞状态的稳态。外分泌再生的开始是通过向祖细胞样表型的腺泡向导管化生完成的，这一机制也在致癌kras驱动的小鼠模型的早期癌变中发现，这可能主要由表观遗传调控的基因表达谱决定。在本研究中，我们旨在研究内在上皮Tlr3信号在胰腺再生和早期癌变中的功能作用，以及激活的Tlr3信号对表观遗传重塑蛋白及其功能的影响。条件小鼠模型和原代分离的腺泡细胞培养将是计划实验的主要内容。

An inflammatory microenvironment plays a major role in tumor initiation and progression and is well documented in pancreatic carcinogenesis. Although the function of Toll-like receptor (Tlr) signaling is highly debated to coordinate innate immunity for early pathogen detection of immune cells, the purpose of an activated Tlr3 signaling pathway in non-immune cells remains elusive. Tlr3 signaling is induced by the recognition of pathogen- or damage-associated molecular patterns (PAMPs or DAMPs, respectively), such as double-strand RNA and promotes a type I interferon response through the activation of downstream pathway components Irf3 and Irf7. Own previous generated data have demonstrated that global Tlr3 and Triflps2 knockout mice reveal increased exocrine cell damage after cerulein-mediated pancreatitis whereas the re-expression of progenitor genes can be accelerated by type I interferon treatment of pancreatic epithelial cell explants. In this respect, we hypothesize that the intrinsic Tlr3 signaling of pancreatic epithelial cells might influence acinar cell homeostasis towards a progenitor-like cell status during the pancreatic regeneration process. The beginning of exocrine regeneration is accomplished by acinar-to-ductal metaplasia towards a progenitor-like phenotype, a mechanisms which is also found in early carcinogenesis of oncogenic Kras-driven mouse models and which might be mainly determined by epigenetic regulated gene expression profiles. In this proposal we aim at examining the functional role of intrinsic epithelial Tlr3 signaling in pancreatic regeneration and early carcinogenesis as well as the influence of activated Tlr3 signaling on epigenetic remodeler and their function. Conditional mouse models and primary isolated acinar cell cultures will be the mainstay of the planned experiments.