Project Details
Projekt
Role of stress response kinases in regulating cell death and subsequent release and action of DAMPs in the pathogenesis of MASH
Subject Area
Gastroenterology
Term
since 2026
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 546585894
The vicious cycle of cell death, damage response, inflammation, and subsequent impaired repair is a key factor in the development and progression of metabolic steatohepatitis (MASH). The relative contributions of the various forms of cell death, the resulting damage molecule patterns (DAMPs), and the underlying intra- and intercellular signaling networks and the immune or inflammatory mechanisms they control are only partially understood. It is generally accepted that the protein kinase MK2 plays a central role in the regulation of inflammatory responses. Findings from the working group now suggest that MK2 plays a more complex role in the development and progression of MASH that cannot be reduced to its functions in the regulation of inflammatory responses. Based on this, P08 aims to systematically elucidate the significance of MK2 in the context of the stage transitions of MASLD to MASH and its progression to fibrosis and HCC. The hypothesis is that MK2 exerts both protective and harmful functions depending on the cell type investigated and that, depending on the stage of the disease, these functions partially counteract each other's during disease progression. Within the scope of the project, the cell type-specific significance of MK2 will first be characterized 1) for the development of stage-specific DAMPs and the cell death forms involved, and 2) for the control of the immune and inflammatory response depending on the disease stage. Using in vitro and in vivo models, these two overarching questions will be investigated in three complementary work packages, and MK2-dependent DAMP and inflammation signatures will be identified and correlated with clinical stage progression in patient cohorts. P08 is conceptually and methodologically closely embedded in the dangerhep consortium. Conceptual synergies exist with P05, P07, P09 (development and progression of MASH, molecular and immunological mechanisms) and P01-P03 (forms of cell death, DAMP signatures). P08 uses and expands central methodological platforms of the consortium, including 2-photon imaging (C01), proteome and lipidome analyses (P05, P07), and immune cell phenotyping (P09). Close integration into dangerhep and access to a comprehensive methodological and content-linked infrastructure will enable P08 to make a significant contribution to developing an integrative understanding of the role of MK2-dependent damage signals and consecutive immune and inflammatory responses in the stage transitions in the development and progression of MASH to fibrosis and HCC This is particularly relevant given that MK2 inhibition is being discussed as a therapeutic principle for the treatment of tumors and chronic inflammatory diseases and is already being evaluated in clinical trials.
DFG Programme
Research Units
