DrNicholas Kirkby

Dr Kirkby's current work centres around the role of cyclo-oxygenase and related enzyme pathways in cardiovascular disease, cancer, inflammation and immunology and is supported by close collaboration with colleagues at NHLI and international leaders in the field.

COX-1 in the vasculature - COX-1 is ubiquitously expressed throughout the vasculature and in platelets. It is clear that COX-1 in platelets drives thrombosis, and inhibition of this explains the cardioprotective effects of aspirin. The role of COX-1 in the vasculature, however, remains less clear with some in vitro evidence suggesting that vascular COX-1 may have both harmful and protective roles in the cardiovascular system. Now, we are using unique genetic models of vascular COX-1-deficiency to explore the relative importance of these effects in vivo. The aim of this work is not only to clarify the role of vascular COX-1 in cardiovascular health and disease but also to test the idea that targeting COX-1 in blood vessels as well as platelets could improve the therapeutic effects of aspirin. 

Cardiovascular side effects of NSAIDs - Non-steroidal anti-inflammatory drugs (NSAIDs), which work by inhibition of COX-2, are amongst the most widely used drugs worldwide. However, their use is associated with rare but serious cardiovascular side effects including heart attacks and strokes. This has prevented development of new NSAID-like drugs, including for cancer prevention, where NSAIDs have proven benefits. We have identified one candidate molecule as ADMA, an endogenous inhibitor of the cardioprotective NO pathway, which is elevated in people taking NSAIDs and which could explain their cardiovascular toxicity and/or predict those at risk. Most recently, we have created novel lines of renal and vascular specific COX-2 knockout mice to determine the relative roles of these tissues in COX-2 cardiovascular protection.

Rgl1 as a novel inflammatory pathway - Another lead we have identified from global gene expression profiling of COX-2 knockout tissue is Rgl1. Rgl1 is a component of the Ras pathway which is activated by Ras and activates Ral, leading to various biological effects. This pathway is most commonly implicated in cancer development, but we have found it also it is induced during inflammation and has important roles in modulating downstream inflammatory responses and functions in vascular and immune cells. We are now studying these questions using a unique Rgl1-deficient mouse model in the context of vascular inflammatory diseases including atherosclerosis and sepsis.