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 or the colon, cell death is very important as it controls the total number of cells within that tissue, 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 to successfully treat many diseases (e.g. cancer) it is important that 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 of selectively killing target cells while leaving most healthy cells unharmed. We are therefore trying to understand the fundamental mechanisms that regulate the response of target cells and normal cells to cytotoxic agents, as this will help in establishing the ideal choice 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.

Cell death is a fundamental cellular response that plays a crucial role both during development and in the removal of unwanted or damaged cells following stress, injury or infection. Inappropriate cell death regulation contributes to many human diseases, including cancer and autoimmune and neurodegenerative disorders. Proteins/pathways that control cell death have also been identified as defined nodes that form key decision points to regulate the response to toxic insult.
This Programme aims at understanding the fundamental mechanisms of cell death that regulate life/death decisions at the cellular level. By understanding the underlying molecular and cell biology of these processes, we aim to deliver field-changing mechanistic insights into toxicology and disease.
Our research Objectives are to develop a number of strategies including develop a number of strategies including novel ‘in vitro’ reconstituted models which, combined with an integrated molecular, cell biological and proteomics-based approach, place us in a prime position to examine the molecular determinants of cell death.
In particular, we will employ cutting-edge technologies to:
1. obtain novel insights on the regulation and molecular architecture of multiprotein signalling complexes that direct cell fate
2. define signalling networks conferring drug-induced mitochondrial toxicity or cell survival in translational models of hepatotoxicity
3. selectively target nodes of resistance to cell death in patient-relevant 3D tumour models.
The data generated through these integrated approaches will provide novel insights into the fundamental mechanisms of cell death that underlie the response to toxic injury, thus informing strategies to mitigate toxicity of existing therapies as well as newer agents under development.