Project description
New treatments for metabolic liver disease
Metabolic dysfunction-associated steatohepatitis (MASH) is a liver disease affecting up to 6 % of the general population and up to 40 % of obese individuals, often leading to severe liver conditions. Currently, only a single approved treatment exists. The ERC-funded 3DMASH project will study organotypic cultures from MASH patients and matched controls to map tissue interactions and identify new pharmacological targets. By co-culturing metabolically relevant tissues in microphysiological systems and applying network biology methods, the project will uncover extrahepatic signalling pathways that influence MASH disease phenotypes. Additionally, it will screen chemogenomic libraries of G protein-coupled receptors, ion channels and nuclear receptors to identify targets that either activate ‘healthy’ signals or inhibit ‘disease’ cues.
Objective
Metabolic dysfunction-associated steatohepatitis (MASH) is a prevalent liver disease that affects up to 6% of the general population and 15-40% of obese persons. MASH is characterized by intracellular triglyceride accumulation (steatosis), chronic inflammation and hepatocyte injury. Importantly, MASH is prone to progress into liver fibrosis, cirrhosis and hepatocellular carcinoma and, even if diagnosed early, the disease is associated with reductions in life expectancy of 2-4.5 years. Despite tremendous efforts, there are currently no approved pharmacological treatments for MASH. MASH is closely linked to obesity, sarcopenia, dyslipidemia and insulin resistance and it has become clear that adipose tissue, pancreas and skeletal muscle produce important signals that orchestrate hepatic metabolism, inflammation and fibrosis. However, the underlying mechanisms in humans remain poorly understood.
In the 3DMASH project, we will utilize organotypic cultures isolated from patients with a clinical diagnosis of MASH and matched controls to comprehensively map tissue interactions and to identify novel targets for pharmacological interventions. By combining co-culture of metabolically relevant tissues from healthy and diseased individuals in microphysiological systems (MPS) with network biology approaches, we will identify novel extrahepatic signaling that positively or negatively influence MASH disease phenotypes.
Moreover, we will use the established platform to screen chemogenomic libraries of G protein coupled receptors, ion channels and nuclear receptors to identify new pharmacologically accessible targets that activate “healthy” signals or inhibit “disease” cues. This project thus provides a conceptually novel perspective that considers MASH as a complex pathology caused by dysregulated tissue interactions and targets these disease mechanisms, which are neglected by current drug development programs, to finally develop effective treatments.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: https://op.europa.eu/en/web/eu-vocabularies/euroscivoc.
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- medical and health sciencesbasic medicinepathology
- medical and health sciencesclinical medicinehepatology
- medical and health scienceshealth sciencesnutritionobesity
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Keywords
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
17177 Stockholm
Sweden