Project 442960

Arthritis is a collection of more than 100 debilitating diseases affecting the joints and surrounding tissues leading to progressive dysfunction of the affected joints and causing an incredible burden on the Canadian healthcare system. Noninflammatory and Inflammatory Arthritis are the two most common forms of the condition. It has been estimated that 1 out of 4 Canadians, and as much as 3 out of 1000 children under the age of 18 years old, will be living with arthritis and diminished quality of life by 2040. Even though current therapeutic resources have been rapidly expanding, arthritis still remains an incurable disease with lifelong health repercussions. Worldwide, rheumatologists are actively working to pursue the identification of markers of arthritis to refine treatments. Genetic markers are especially appealing as they account for close to 65% of rheumatoid arthritis heritability, one of the most common forms of inflammatory arthritis. We identified a family of patients with a genetic mutation causing the DICER protein to be dysfunctional. Patients from this family had features of a dysfunctional immune system with increased susceptibility to infections, as well as arthritis. Surprisingly, blocking the activation of the immune system, with a drug called Abatacept, resolved the arthritis and restored normal antibodies production in these patients. Our general aim is therefore to depict the role of the DICER protein in the development of inflammatory arthritis. More specifically we want to understand how DICER loss affects the development of the immune system and triggers arthritis. Furthermore, we aim to understand the mechanisms by which Abatacept is able to restore antibody production. Our program will thus allow for the identification of new putative therapeutic targets and refine our understanding of autoimmunity, as well as its treatments.