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TRR 412:  Metabolic dysfunction-associated steatotic liver disease: Translating mechanisms to tailored therapeutic concepts

Subject Area Medicine
Term since 2025
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 535081457
 
Metabolic dysfunction-associated fatty liver disease (MASLD) is the most common chronic liver disease worldwide, affecting a staggering 30% of the general population, with further rise in prevalence in an ageing and more obese world population. MASLD constitutes a major cause of life-threatening sequelae such as liver cirrhosis or hepatocellular carcinoma. While interventions targeting underlying metabolic risk factors like obesity and insulin resistance, primarily through weight loss, have shown some effectiveness, weight-lowering drugs such as semaglutide offer limited benefit for liver fibrosis. Liver-targeted pharmacotherapies have largely failed to yield promising results. The Transregio-CRC (CRC/TR) 412 will focus on understanding, preventing and treating MASLD before the development of late stage complications as decompensated liver cirrhosis or hepatocellular carcinoma. Our consortium seeks to leverage innovative multi-omics and spatial technologies, together with outstanding immunological, clinical and translational expertise, to provide yet unprecedented insight into MASLD-driving cell interactions and pathomechanisms in patients, followed by subsequent functional validation as well as testing of new therapies in experimental models. Our interdisciplinary research consortium will focus on a bidirectional bedside-to-bench and bench-to-bedside approach defining and targeting mechanisms that drive the transition from metabolic risk to overt disease with liver-specific sequelae and adverse prognosis. The overarching aim is to gain a holistic understanding of the disease-defining, liver-specific molecular and cellular events in metabolic dysfunction-associated fatty liver disease. Projects organized in two interrelated research areas (A – metabolic injury, B – inflammation and fibrosis) aim to understand heterogeneity in mechanisms of hepatocyte metabolic injury, subsequent inflammatory and fibrogenic responses as well as the underlying cell-cell crosstalk in order to develop novel therapeutic concepts. Central projects will provide relevant cross-sectional technologies such as access to extensively phenotyped patient material, transcriptomics, bioinformatics, science data management and an integrated research training group. Together, we will define the events and key players that govern the transition from benign steatosis to metabolic dysfunction-associated steatohepatitis (MASH); understand key drivers of hepatic inflammation and the cross-talk between different cell-types, fibrogenesis and how they converge to interrelated feed-forward mechanisms in MASLD, and apply the above concepts to develop novel therapeutic approaches and concepts of multi-modal combination therapy in MASLD. Conclusion: The CRC/TR 412 in Berlin and Dresden will open prospects for a new generation of rationally designed and personalized treatment approaches that might prevent the liver of at-risk individuals progress from metabolic risk to disease.
DFG Programme CRC/Transregios

Current projects

Applicant Institution shared FU Berlin and HU Berlin through:
Charité - Universitätsmedizin Berlin
Participating University Eberhard Karls Universität Tübingen
 
 

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