Zebrafish genetic approaches to understanding the regulation of inflammatory cell apoptosis.

In many inflammatory diseases, white blood cells called neutrophils cause damage to tissues. Examples in the lung include common conditions such as COPD, asthma and interstitial lung diseases. Current treatments are poorly effective and have many side effects. Neutrophils normally fight infection, but can also harm tissues if inappropriately activated and in health this is prevented by programmed cell death (apoptosis), which allows their removal. This process is blocked in inflammatory disease. I am looking for ways to circumvent this block and thus suppress the inflammatory response. Apoptosis is regulated by activation of a group of specialised enzymes called caspases in various types of caspase activating platform (CAP) - complexes of proteins that regulate activation of caspases. I propose apoptosis is regulated in a unique way in neutrophils, by activation of specific caspases in a new type of CAP. I will explore this idea using a model of the inflammatory response I have developed in the zebrafish. This organism allows us to observe neutrophils in living animals and to screen for genetic mutations or chemicals that modify neutrophil behaviour. In this way I aim to discover the genes that control neutrophil apoptosis and develop new drugs to treat inflammatory disease.