Project 171733

This proposal is aimed at identification of the genes/proteins which confer susceptibility to rheumatoid arthritis (RA). RA is a chronic inflammatory disease in which the tissues lining the joints become severely inflamed and ultimately damaged. As a result most patients experience systemic illness and chronic pain and disability, requiring frequent hospitalizations and surgical interventions. At present treatment of RA is far from satisfactory, such therapy often being unsuccessful and/or associated with considerable toxicity. Development of better treatment or preventive strategies in RA has been impeded by lack of understanding of the basic cause(s) of this disease. However, a major role for genetic factors in development of RA is widely recognized. The goal of this proposal is to identify these genetic factors using DNA markers to compare RA patient gene status with that of healthy controls. We have already identified several regions of the genome which appear to harbor RA risk genes. We will now characterize these regions in detail so as to pinpoint the gene lesions causing RA. Once identified, the susceptibility genes and the proteins they encode will be studied for their effect on disease risk as well as severity and outcome. We will also focus on characterizing the molecular pathways linking one known RA risk variant to disease. These data will pave the way for earlier diagnosis, improved therapy and, ultimately, prevention of RA.