MRC TS Award: Regulation of neutrophil functions by cell cycle proteins

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Neutrophils are the most abundant immune cells in the blood and they are essential for defending us against disease-causing microbes. They are considered the 'first line of defence' in response to infection or wounding. Neutrophils have several ways of destroying microbes to prevent the infection from spreading. They can engulf microbes or produce antimicrobial chemicals. Neutrophils can also release "NETs" - Neutrophil Extracellular Traps. NETs consist of webs of DNA that are adhesive and also contain toxic antimicrobial proteins; NETs trap microbes and prevent them from spreading away from the site of infection. They also help to amplify inflammation and to recruit additional immune cells.NET release must be carefully controlled because excessive NET formation can also damage our own cells and tissues. In fact, neutrophils are often hyperactivated in many non-infectious inflammatory diseases. Excessive NET formation is thought to contribute to autoimmune diseases such as lupus, rheumatoid arthritis and asthma, as well as cancer and atherosclerosis (which can cause stroke and heart attack).If we could understand how NETs formation is regulated, we could potentially develop therapies to boost NET formation when the body needs to prevent infections or, conversely, to block their release when they are causing pathological inflammation. The aim of this proposal is to complete undergoing studies that aim to understand which proteins control NET release. We discovered that some proteins that normally control cell division are also involved in regulating NET formation. We now propose to undertake detailed studies to understand exactly how these proteins function in NET formation. We will do this by analysing which additional proteins the regulators interact with, and what aspects of cellular biology they affect.Completing these aims will give us a better understanding of the molecular mechanism of NETs. It would also help to establish my group as international experts in the field of neutrophil biology, allowing us to tackle important global health issues.