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

• Applicant: Dr. Ivonne Regel
• Subject Area: General and Visceral Surgery ; Gastroenterology ; Cell Biology
• Term: from 2015 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 281544179

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.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Christoph Michalski