Saturday, April 27, 2024
4/27/2024
Project Summary/Abstract Fibroblasts are key aggressors in rheumatoid arthritis (RA) where they mediate cartilage and bone destruction, yet treatments that directly target these cells are lacking. Recent studies from our group and others have shown that the expansion of an inflammatory subset of fibroblasts are critical to perpetuating the chronic inflammation in RA, but mechanisms responsible for their inflammatory potentiation are not well-defined. Our preliminary studies have revealed that synovial fibroblasts are uniquely poised to signal through the Wnt pathway and further demonstrate that Wnt induces a strong inflammatory response in these cells. Notably, there is a striking transcriptional gradient demarcated by a Wnt enhancer, R-spondin 3 (RSPO3), and a putative Wnt inhibitor, Dickkopf-related protein 3 (DKK3), that correlates with Wnt pathway enrichment. We find that synovial fibroblasts derived from active RA patients show enrichment of gene signatures associated with Wnt activation and Rspo3 expression, suggesting relevance to arthritis manifestation. We hypothesize that Wnt signaling through this gradient is critical for mediating inflammatory fibroblast pathogenicity and that Wnt inhibition can ameliorate joint damage in RA. We develop our hypothesis in three independent aims. In Aim 1, we define the role of Rspo3 and Dkk3 in regulating Wnt-induced synovial fibroblast activation in vitro using ligand stimulation and knockdown techniques. In Aim 2, we assess Rspo3 and Dkk3 regulation of Wnt signaling in synovial fibroblasts of distinct RA patient clinical and histologic phenotypes. Finally, in Aim 3, we evaluate the clinical utility of targeting stromal Wnt signaling therapeutically in mouse models of inflammatory arthritis. We anticipate that the significance of these studies will be to elucidate a molecular mechanism contributing to fibroblast pathogenicity in RA and to address the unmet need for fibroblast-specific therapeutics. These studies will provide training in immunology, bioinformatics, and murine models of inflammatory arthritis that that will build a foundation for the PI to develop an independent lab studying the role of stromal cells in autoimmune disease.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
