Refining the study of fatigue in mouse models of chronic liver disease

Fatigue is a common and frequently debilitating symptom that occurs in a wide variety of chronic liver diseases such as Primary Biliary Cirrhosis.  Unfortunately it also is very difficult to treat. There is therefore a critical clinical need to elucidate disease mechanisms and develop therapies that alleviate the symptom of fatigue. Rodent models are invaluable in this process but unfortunately in vivo fatigue studies typically have a considerable impact on the animals involved. The main objective of this project is to refine the study of fatigue in mouse models of chronic liver disease by developing more sensitive, less invasive methods of assessing fatigue. As an alternative to methods such as the forced swim test that have been used to assess fatigue, in this project mice will be assessed using a transponder-based automated homecage. This approach has both welfare and scientific benefits as the multi-faceted components of fatigue will be continuously, non-invasively assessed in animals that are socially housed in an enriched environment. Because of the similarities in many symptoms of fatigue regardless of aetiology, the assessment techniques developed in this project will be applicable to in vivo research on the fatigue of other origins. Early markers of ill health or poor welfare applicable to other murine disease models will also be identified in this project.

A further objective of this project, through collaboration with the Newcastle liver research group, will be to identify refined animal models. The bile duct ligated (BDL) rodent model has most frequently been used to study fatigue in chronic liver disease however the BDL procedure has a substantial impact on the animals examined. Many of the mouse models already being studied for other purposes in our animal unit are less invasive than the BDL model, likely to be more appropriate models of chronic fatigue and will not need to be used specifically for this project. Ageing nuclear factor κΒ knockout mice for example, show particular promise as an alternative, non-invasive model of Primary Biliary Cirrhosis.