Grant: CIHR Fellowship

Rheumatoid Arthritis (RA) is one of the most common inflammatory disorders in developed countries, with approximately 460 cases per 100,000 individuals. It is usually characterized by joint swelling and stiffness, pain, as well as fatigue. Though the exact cause of RA is still under debate, current evidence suggests that it is a consequence of complex interactions between genetic and environmental factors. Due to this multifactorial origin, treatment of RA is challenging and currently demands an individualized approach that requires close monitoring of disease activity. Because efficacy of current treatments is varied and can cause serious side effects, there is an urgent need to better understand the disease to develop more effective and safer therapies. Granzymes are molecular scissors that cleave or degrade numerous proteins, inside and outside of cells, and are usually undetectable in blood or tissues of healthy individuals. In recent years, it has been shown that the levels of granzymes, and especially granzyme B, are elevated in inflammatory conditions of the skin, eyes, lungs, muscles, among other tissues. There is also increasing evidence that granzyme B levels are elevated in blood and joint fluid of patients suffering from RA and are correlated with disease severity. Nevertheless, little is known about the exact function of granzyme B in the development or progression of RA. In the proposed study, I will investigate the role of granzyme B in RA using experimental models and samples from patients with RA. Therapeutic efficacy of a granzyme B-inhibiting drug (previously demonstrated as safe and efficacious in other models) will also be investigated in an experimental model for joint inflammation. Results from this work will increase current knowledge on the role of granzyme B in RA and will support the development of its inhibitor into a treatment for RA, in addition to other inflammatory disorders associated with aberrant granzyme B activity.