Project 442963

Rheumatoid arthritis (RA) is one of the most prevalent chronic inflammatory disorders in North America; it currently affects about 300,000 Canadians, and costs our economy a staggering 5.8 billion per year in direct and indirect costs. RA is characterized by a chronic inflammation of the joints and a progressive destruction of cartilage and bone. It is painful, incapacitating, and incurable. 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, and that perpetuate the inflammatory state. Recent studies made in animal models strongly support this view. In this proposal, we will focus our efforts on a cellular signaling protein that controls the production of chemokines by neutrophils in response to inflammatory biochemicals in the micro-environment. This protein (the TAK1 kinase) has many unique features in neutrophils, and we aim to identify key molecular partners of TAK1 that can be exploited for future 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 arthritic diseases.