Recent evidence suggests an essential contribution of neutrophils in immunity, inflammation and cancer that extend far beyond their well-known anti-microbial responses. This evidence includes their ability to release extracellular DNA structures. The release of extracellular DNA leads to externalizing enhanced levels of putative autoantigens, and is considered to be particularly relevant to neutrophil deleterious roles in rheumatic diseases. This phenomenon is currently collectively referred to as neutrophil extracellular trap (NET) formation.
PAD4 is an enzyme capable of citrullinating proteins that is being considered as an interesting therapeutic target in rheumatic disorders. The primary interest is to determine whether PAD4 inhibition impacts NET formation in human neutrophils in response to disease-relevant stimuli and to determine whether sub-populations of patients are more prone to citrullination-associated NETosis and thus more likely to respond to a PAD4 inhibitor. Mechanistically, NET formation has been linked to a programmed genome disassembly that is precisely organised and sequence programmed at the level of chromatin organisation.
Speaking of the award, Tariq commented “Ultimately, our aim is to define an early signature in peripheral neutrophils that would correlate with disease severity and propensity to form NETs and can easily be detected in human serum or blood.”
The fellowship starts in November 2017 and runs for 36 months.