Project Details
Projekt
Exploring the function of apoptotic effector Caspases in stage transitions of hepatic diseases
Applicant
Dr. Anne Theres Schneider
Subject Area
Gastroenterology
Term
since 2026
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 546585894
Chronic liver diseases such as metabolic-associated steatohepatitis (MASH) progress through stages from steatosis to inflammation, fibrosis, and ultimately hepatocellular carcinoma (HCC). Programmed death of hepatocytes is a key driver of this progression, as it triggers inflammatory responses and compensatory proliferation through the release of specific danger-associated molecular patterns (DAMPs). Different forms of programmed cell death influence the course and severity of liver disease. While apoptosis is the best-characterized form of cell death, its specific role in the transition from chronic inflammation to tumor development remains largely unclear. Preliminary data from our group indicate that apoptosis can promote inflammation and thereby contribute to hepatocarcinogenesis, a finding that challenges the dogma of immunologically “silent” apoptosis. Moreover, apoptotic caspases fulfill complex, context-dependent functions that need to be dissected in detail. Project P02 builds on these findings and focuses on effector caspases in the transition from MASH to HCC, aiming to uncover novel mechanisms and identify potential therapeutic targets. We hypothesize that effector caspases not only induce cell death, but also orchestrate the release of specific DAMPs that shape immune cell recruitment, tissue regeneration, and tumor formation. The project is structured into four modules: (i) Characterization of expression and activity patterns of effector caspases in various stages of experimental liver disease; (ii) functional in vivo investigation of effector caspases in the progression from MASH to HCC; (iii) analysis of caspase-associated morphological features in the liver using intravital two-photon microscopy; (iv) translation of findings to patient cohorts by correlating DAMP signatures with clinical disease stages. P02 is tightly integrated within dangerhep. Synergies exist with P01, P03, and P04 (comparative analysis of different forms of programmed cell death and DAMP release), P07 (sphingolipids as apoptotic DAMPs), and P09 (caspase-dependent mechanisms in MASH/HCC). P02 utilizes central platforms such as two-photon microscopy (C01), precision-cut liver tissue slices (P03), proteomics and lipidomics platforms (P05, P07), and the biobank (P08). In addition, P02 contributes the HMGB1-mCherry reporter mouse line, an innovative tool for dynamic in vivo analysis of DAMP release. P02 is designed to significantly advance the functional understanding of apoptotic cell death in chronic liver disease. The overall aim is to better define apoptosis-mediated danger signaling at disease stage transitions, to conceptualize apoptosis as a controllable source of inflammatory and regenerative responses, and to derive novel diagnostic and therapeutic strategies for patients with chronic liver disease.
DFG Programme
Research Units
