Project Details
Projekt
Autophagic and Epigenetic Control of Liver-Directed Gene Therapy with Adeno-Associated Viral Vectors
Subject Area
Gastroenterology
Parasitology and Biology of Tropical Infectious Disease Pathogens
Parasitology and Biology of Tropical Infectious Disease Pathogens
Term
from 2020 to 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 431535912
Our overall goal is to characterize in detail the unique AAV/liver interaction and to use this knowledge to improve the efficiency and the safety of liver-directed gene therapy with rAAV vectors. Here, we aim to focus on two fundamental new aspects with major implication: I) Liver-specific autophagic and epigenetic regulation of rAAV genome transcriptionWe demonstrated that rAAV induce autophagy in hepatocytes and that this response is required for efficient transduction of hepatocytes in vitro and in vivo. Furthermore, we showed that increasing the basal (physiological) level of autophagy in hepatocytes markedly improves rAAV transduction efficiency by a mechanism which - based on our preliminary results – likely involves hepatocyte-specific epigenetic regulation of rAAV mRNA transcription. Here, we aim to investigate whether autophagy activates hepatocyte-specific transcription factor HNF1α leading to recruitment of histone modifying complexes which in turn contribute to the establishment of a transcriptionally active rAAV chromatin state. II) Toll-like-receptor (TLR) 2-mediated sensing of rAAVs by liver NPC and induction of IL-6/autophagy signaling in hepatocytes which promotes rAAV transductionWe identified TLR2 as sensor of AAV capsids in human non-parenchymal liver cells. As shown in our preliminary results, this response leads to secretion of IL-6 which in turn positively influences rAAV-mediated transgene expression in hepatocytes. We hypothesize that this promoting effect involves STAT3- and AMPK-dependent activation of hepatocellular autophagy and can also be mediated through a direct HNF1α-pSTAT3 interaction. Here, we aim to investigate this hypothesis and decipher the respective pathways and mechanisms.
DFG Programme
Research Grants
