Identifying TRAF1 Mutations as a Key Step to Develop a Targeted Therapy for Rheumatoid Arthritis

Rheumatoid Arthritis is an autoimmune disease characterized by chronic inflammation. Tumor necrosis factor receptor (TNFR)- associated factor 1 (TRAF1) has been implicated in disease development. TRAF1 is a signalling adapter downstream of TNFR and Toll-like receptors (TLR), where it plays opposing roles in the activation of nuclear factor-k-B, NF-κB. Downstream of TNFRs, TRAF1 acts as a positive regulator of NF-κB, whereas downstream of TLRs, TRAF1 acts as a negative regulator of NF-κB. TRAF1 negatively regulates NF-κB by sequestering the Linear-Ubiquitin Assembly Chain Complex (LUBAC). Recent work in the lab has identified the exact sites of interaction of human TRAF1 in both these pathways. This thesis aims to investigate and generate a mouse model to study the role of mouse TRAF1 downstream of TLRs and its interaction with LUBAC. TRAF1 truncations and mutants have been developed which will be used to confirm the exact amino acids responsible for this interaction.