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，并且在胰腺癌的发生中有很好的记录。尽管Toll样受体（Tlr）信号传导的功能在协调先天免疫以用于免疫细胞的早期病原体检测方面存在高度争议，但在非免疫细胞中激活的Tlr3信号传导途径的目的仍然难以捉摸。Tlr3信号传导通过识别病原体或损伤相关的分子模式（分别为PAMP或DAMP）（例如双链RNA）来诱导，并通过激活下游途径组分Irf3和Irf7来促进I型干扰素应答。自身先前产生的数据已经证明，整体Tlr3和Triflps2敲除小鼠揭示了在蛙皮素介导的胰腺炎后增加的外分泌细胞损伤，而祖基因的再表达可以通过胰腺上皮细胞外植体的I型干扰素处理来加速。在这方面，我们假设胰腺上皮细胞的内在Tlr3信号传导可能影响胰腺再生过程中腺泡细胞向祖细胞样细胞状态的稳态。外分泌再生的开始是通过腺泡到导管化生向祖细胞样表型完成的，这是一种在致癌Kras驱动的小鼠模型的早期癌变中也发现的机制，并且可能主要由表观遗传调节的基因表达谱决定。在这个建议中，我们的目的是研究内在上皮Tlr3信号在胰腺再生和早期癌变中的功能作用，以及活化的Tlr3信号对表观遗传重塑及其功能的影响。条件性小鼠模型和原代分离腺泡细胞培养物将是计划实验的主要部分。

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.