Determining the relevance of metabolic pathways as a therapeutic target in non-alcoholic fatty liver disease (NAFLD) cirrhosis
LEAD SUPERVISOR: Prof Leanne Hodson, Radcliffe Department of Medicine - OCDEM
Co-supervisor: Prof Jeremy Tomlinson, Radcliffe Department of Medicine - OCDEM
Commercial partner: Ochre Bio, Oxford
Background: Non-alcoholic fatty liver disease (NAFLD), for which men have a higher propensity, is a spectrum of disease ranging from simple steatosis to inﬂammation (non-alcoholic steatohepatitis [NASH]), cirrhosis, and hepatocellular carcinoma (HCC). Despite the burden of disease (one in four adults have simple steatosis), there are currently no licensed treatments for NAFLD. Therapeutic options are limited, with the only effective treatment for end-stage disease (cirrhosis) being a liver transplant. Therapeutic innovation remains particularly challenging for numerous reasons, such as disease silence (thus limited biological understanding), poor predictivity of experimental models, and disease complexity (involving many cell types). Therefore, there is a need to elucidate the key pathways driving disease progression using more physiological and complex models that accurately reflect each stage of disease. This will enable therapeutically relevant intervention and ultimately lower the number of individuals on liver transplant waiting lists.
Aim 1 – To extend the complex in vitro cellular models developed at Ochre Bio and Hodson labs to include fibrosis induced by metabolic stress. Current models recapitulate many aspects of disease progression but it is imperative for therapeutics focused on metabolic regulation to have suitable models that recapitulate all aspects of cirrhotic progression. The models will be fully characterised transcriptomically using the expertise from Ochre Bio (e.g. scRNAseq, to understand the contribution of different cellular populations in disease progression) and metabolically phenotyped using the expertise within the Hodson lab (e.g. stable isotope tracers to study lipid and glucose biogenesis). To demonstrate the accuracy and applicability of these models they will be benchmarked against human livers from the full spectrum of NAFLD (perfused by Ochre Bio as part of their drug discovery efforts), using the extensive array of technologies at the disposal of Ochre Bio and the Hodson labs.
Aim 2 - Ochre Bio has already built an early disease progression atlas database, by RNA sequencing 1000 human livers that highlighted a number of genes that demonstrated sexual dimorphism. These genes will be confirmed within the perfused livers of more advanced disease stages and then assessed for disease modifying behaviour using siRNA technology within the models generated in aim 1. This will provide gene candidates for future development as treatment modalities.
The proposed project not only addresses a number of MRC priorities including: prevention and early detection (by understanding the full progression of disease and targeting the metabolic underpinnings), precision medicine (by investigating genes that show sexual-dimorphism, a key feature of disease risk) and multimorbidities (by studying and targeted the metabolic influencers of disease we will impact on diabetes, CVD risk, inflammation as well as aging, all of which are associated to metabolism), it forms a mutually beneficial research collaboration aimed at addressing the unmet need for human models recapitulating human NAFLD. Not only will this help improve our understanding of the biology of this disease, but it provides a physiologically-accurate tool for developing NAFLD therapeutics.
Apply using course: DPhil in Medical Sciences