Grant: Operating Grant

Gout is a form of arthritis, a disease which is one of the most prevalent chronic inflammatory disorders in North America; about 1 in 50 people will develop gout over a lifetime. Gout is characterized by a chronic inflammation of the joints and a progressive destruction of cartilage and bone. It is a painful and incurable process. One of the distinctive features of arthritic joints is their massive infiltration by white blood cells, and in particular neutrophils. The latter have been proposed as a source of several inflammatory mediators (including cytokines) that are present at high levels inside inflamed joints. A recent study, which found that neutrophils are indeed essential to the initiation of arthritis in a murine model, strongly supports this view. In this proposal, we focus our efforts on cellular signaling intermediates that control the production of cytokines by neutrophils in response to the causative agent of gout, i.e. monosodium urate (MSU) crystals. We have recently identified new cellular intermediates (mainly kinases) that are involved in this important neutrophil response, and we suspect that under conditions that closely mimick the physiological context in which neutrophils interact with MSU crsytals, more such intermediates will be unveiled. From this work, key regulators will emerge, that can be exploited for therapeutic intervention. Accordingly, we believe that molecule-driven strategies, such as the ones we propose herein, have the potential to reap important benefits for the health of Canadians, and in particular ageing citizens, who are most susceptible to suffer from painful acute gout attacks.