In the first funding period, we have established the experimental and computational framework for generating single cell-resolved atlases of adipose and hepatic tissues in mouse models and humans. We have successfully used this setup to report the first complete atlas of adipose tissue and to discover cellular transitions and molecular mechanisms contributing to disease etiology in adipose tissue and liver of obese mice as well as in humans. Furthermore, we have used our interdisciplinary platform to identify novel biomarkers and potential therapeutic targets of human metabolic associated fatty liver disease (MAFLD).
In the extension of our center (ATLAS 2.0) we aim to gain systems‐level, mechanistic understanding of the plasticity of human adipose and hepatic tissues at single cell spatial resolution in response to severe obesity and regression. We will use this insight to uncover disease mechanisms, and to map disease trajectories of human obesity comorbidities, specifically MAFLD.
WP1: Molecular and cellular mechanisms of adipose tissue plasticity in the context of obesity
The overall aim is to determine the molecular mechanisms, including the transcriptional drivers, involved in cellular plasticity and differentiation in human adipose tissue in obesity and weight loss. We will also investigate the role of the tissue micro-environment and investigate cellular crosstalk.
Work Package leader: Mandrup
Partners: Schmidt, Loft, Brewer, Madsen, Lauridsen, Krag, Blagoev
Key collaborators: Claussnitzer, Karpe, Loos
WP2: Molecular and cellular mechanisms of hepatic tissue plasticity in the context of obesity
The overall aim is to determine the molecular mechanisms regulating cellular plasticity in the liver and determine the role of tissue architecture and the cellular niche in MASLD progression and resolution.
Work package leader: Ravnskjaer
Partners: Grøntved, Graversen, Brewer, Madsen, Lauridsen, Krag
Key collaborators: Henderson, Waterfall, Moestrup
WP3: Mechanisms of healthy and unhealthy adipose tissue in obesity
The overall aim of this Work Package is to determine molecular and genetic mechanisms underlying inter-individual variation in susceptibility to adipose tissue dysfunction in human obesity. To this end we will link cellular heterogeneity in the adipose tissue with clinical heterogeneity in different human cohorts to identify key molecular drivers and genetic mechanisms of adipose dysfunction.
Work package leader: Schmidt
Partners: Loft, Mandrup, Lauridsen, Krag, Blagoev, Ravnskjær, Grøntved, Graversen, Madsen
Key collaborators: Claussnitzer, Karpe, Loos, Højlund, Babu
WP4: Disease trajectories and biomarkers
The overall aim is to map molecular disease trajectories of MASLD through multi-modal data integration. Leveraging these deep molecular insights, we plan to construct sophisticated algorithms capable of predicting disease trajectories and outcomes.
Work package leaders: Madsen, Lauridsen
Partners: Mandrup, Graversen, Blagoev, Ravnskjær, Grøntved
Key collaborators: Babu, Claussnitzer, Karpe, Loos, Højlund