DESCRIPTION (provided by applicant): The proposed studies continue a decade-long and productive research program supported by AI64350. The overall theme remains on the molecular mechanisms and biomedical significance of the host response to tissue injury. Based on our exciting preliminary data, we will explore a new frontier in this research, i.e., how to tap into the potential of Siglec-mediated negative regulation of the immune response to treat rheumatoid arthritis. Siglecs are lectin Ig superfamily members that recognize a variety of sialic acid-containing structures. The majority of Siglecs have intracellular domains that contain several immune tyrosine inhibitory motifs (ITIMs) that associate with SHP-1, -2 and Cbl inducibly. In the last funding period, we demonstrated that Siglec G interacts with sialylated CD24 to suppress the TLR-mediated host response to danger (damage)-associated molecular patterns (DAMPs) in aseptic tissue injury and sepsis. More recently, our collaborative work demonstrated that Siglec G associates with Cbl to trigger degradation of RIG-I, resulting in suppression of the type I interferon response. Given the prominent role of these pathways in the pathogenesis of autoimmune disease, we hypothesize that the Siglec-CD24 interaction suppresses autoimmune disease and can thus be fortified for autoimmune disease therapy. In preparation for the renewal of this project, we have obtained substantial unpublished data that reveal the role for sialoside-based pattern recognition in the pathogenesis and treatment of rheumatoid arthritis (RA). We have demonstrated that a fusion protein consisting of human CD24 and IgG1 Fc is highly efficient in suppressing both collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA). Our genetic studies suggest that this therapeutic effect is partially dependent on Siglec G. The disparity between Cd24 and Siglecg mutations in their impact on RA severity suggests that additional CD24 receptors exist. Based on these exciting results, we hereby propose to comprehensively elucidate the role of Siglecs in the pathogenesis and therapy of RA. As a logical progression, we will investigate the biochemical mechanism and genetic requirement for ITIM-containing and DAP12- binding Siglecs in both the severity and therapeutic response to RA using both CIA and CAIA models. Our proposed studies also involve the generation of new animal models with simultaneous deletions in multiple closely linked genes using the new Cas9-based gene deletion in zygotes. If successful, these proposed studies may provide a new paradigm to study the overlapping function of sialoside-based pattern recognition receptors and provide a missing link between Siglecs and RA.

PUBLIC HEALTH RELEVANCE: Our proposed studies will not only elucidate the biochemical and genetic mechanism for the CD24-Siglec interaction in the pathogenesis and therapy of RA, but may also provide new targets and therapeutic agents to address the unmet medical need in RA therapy.