In vivo perturbation and imaging to characterise causal genes and therapeutic targets for fatty liver disease

The purpose of this project is to improve our understanding of non-alcoholic fatty liver disease (NAFLD) aetiology and identify targets for efficient and safe treatment and prevention of disease progression.

Specifically, I aim to prioritise (year 1) and characterise (years 1-3) 120 genes for a role in liver fat accumulation using CRISPR/Cas9-, in vivo imaging, and deep learning-based image analysis in zebrafish larvae.

The most promising genes will be characterised further for a role in hepatic inflammation, stellate cell activation and fibrosis; and trait related to diabetes, atherosclerosis, kidney morphology and function, and heart rhythm and rate (year 4).

For genes encoding promising targets, a role in liver fat accumulation will next be examined using additional gene perturbation methods (year 5).For each candidate gene, we will compare image-based traits in 50 crispants and 50 sibling controls per condition, in overfed larvae with/without additional challenges with extra dietary cholesterol and glucose.Only a handful of genes are currently robustly implicated in NAFLD aetiology, and there are no FDA-approved drugs.

At the same time, the global prevalence of NAFLD is 32.4% and rising, and it is projected to become the leading cause of liver transplantation in the next 10-years. Hence, this project has the potential for very high clinical significance.