Grant: Project Grant

Rheumatoid arthritis (RA) is a painful, lifelong autoimmune disease that affects millions worldwide. Current treatments help some patients, but many experience incomplete relief or serious side effects. To develop better, more precise therapies, we need to understand the key immune signals driving RA. One important player in RA is a protein called TRAF1. Genetic studies have linked TRAF1 to an increased risk of RA, but its exact role in inflammation has been unclear. Our research has uncovered a critical new function for TRAF1-it acts as a molecular switch, either promoting or reducing inflammation, depending on the proteins it interacts with. When TRAF1 binds to a protein called cIAP2, it fuels inflammation in immune cells like T cells, B cells, and macrophages. This worsens joint swelling and damage in RA. When TRAF1 interacts with another protein, LUBAC, it has the opposite effect, helping to calm excessive inflammation. We recently discovered that changing a single amino acid in TRAF1 can block its interaction with cIAP2, shifting the balance toward reduced inflammation. Mice with this mutation had less joint swelling and were protected from severe inflammation. Building on these findings, we will: Study TRAF1's role in RA to identify the immune cells and signals most affected by its interactions. Develop new treatments that block TRAF1/cIAP2 binding while preserving TRAF1's ability to control excessive inflammation. By using state-of-the-art imaging and drug discovery techniques, this research aims to unlock new ways to treat RA, offering more effective and targeted therapies with fewer side effects.