Molecular Mechanisms of Cell Death.

Diseases such as cancer and neurodegenerative disorders are characterised by a significant alteration in the total number of cells within the tissue. This may result from increased division of cells and/or may arise from a defect in cell death regulation. In tissues such as the lymphoid system cell death is important as it controls the total number of cells, whereas in the nervous system inappropriate cell death is catastrophic. Consequently, cell death in these situations is tightly controlled and often occurs in an ordered manner by a process called ‘apoptosis’, or a more recently identified mode of cell death termed ‘necroptosis’. We are studying these cell death processes because adverse outcomes (toxicity) associated with therapeutic drugs are often mediated by the proteins/pathways that control cell death, whereas to successfully treat some diseases (e.g. cancer) it is important we find ways to switch ‘ON’ cell death. However, it is crucial to first understand the basic mechanisms that regulate cell death in order to identify ways to leave most healthy cells unharmed. We are therefore trying to uncover the fundamental mechanisms that regulate the response of normal and/or target cells to therapeutic agents, as this will help in establishing the ideal choice of agents for the treatment of disease. Our aim is to establish better predictive models of mitochondrial toxicity, providing mechanistic frameworks to facilitate safer drug development and potentially alleviate the toxic effects of existing treatments.