NWO Complexity "Complex Systems Framework for Non-alcoholic fatty liver disease (NAFLD)

One of the most prevalent diseases linked to obesity is Non-Alcoholic Fatty Liver Disease (NAFLD), which is characterized by accumulation of fat droplets in the liver and gradual progressing into disease stages with advancing levels of inflammation and fibrosis, eventually resulting in a potential fatal outcome. The mechanisms behind the initiation and progression of the disease are still poorly understood, which hampers the development of effective treatments and prevention strategies. Therefore, this project is focusing on the development of a novel research strategy that allows describing cellular and molecular changes that occur during the development of the disease in a computational model. This ‘Complex Systems Framework’ will be applied to a new set of data that will be generated using an innovative cell culturing system using human primary hepatocytes that are chemically induced to develop an increasingly severe disease phenotype over time.  Additionally, ‘cell-painting’ technologies will be used to visualize phenotypic endpoints at the subcellular level, which will guide the identification of crucial transitions in the development of NAFLD.  At these transitions, gene expression analysis using RNA-sequencing will be performed to obtain insight in the molecular processes accompanying these disease state transitions. Based on the detailed description of the processes involved in transitions during disease progression, a mathematical model will be constructed that integrates both cellular and molecular features. This model will be applied for the identification of molecular targets for disease treatment and prevention and allows for the design of more effective and individually tailored food-based intervention strategies.