Rheumatoid arthritis (RA) is the most common autoimmune disease which affects 2.5 million people in the US, many of which are VA military personnel. One in four veterans has arthritis (25.6%), compared to one in five civilians. RA is a chronic, disabling autoimmune disease in which the body attacks its tissues. As RA progresses, performing simple daily activities becomes increasingly difficult for patients suffering from the disease. Presently, there is no cure for RA and up to 50% of patients diagnosed with RA do not respond to current treatments or lose their responsiveness over time. Findings that lead to new therapy will benefit the VA personnel by reducing the cost of medical and surgical care; in addition to the secondary RA complications including depression, cardiovascular disease, and psychosocial stress. Consequently, effective RA therapy will improve the pain & the life quality of veterans. The goal of this project is to identify novel therapeutic targets for patients that do not respond to current treatments. As such, we have uncovered novel pathways that can markedly alleviate pannus formation by disconnecting the unique networks interconnecting RA inflammatory macrophages to joint neovasculature via metabolic reprogramming. Unlike the current RA standard of care, the mechanism of action is not limited to a specific inflammatory factor and its function will impact multiple cell types in the RA pannus and their metabolic crosstalk. We are proposing a unique way of negating RA pannus formation which has not been examined previously. Initially, we will examine the inflammatory & metabolic profiles of RA circulating blood and synovial tissue macrophages in response to an identified endogenous factor to delineate if blockade of hypermetabolic activity will reverse the inflammatory phenotype by RNA-sequencing and CyTOF. Next, the impact of the endogenous factor will be determined on endothelial cell metabolic reprogramming and their cross-regulation with RA macrophages by comparing cells in monoculture with the coculture condition employing isotype labeling of carbon flux, mitochondria tracker, and real-time ATP assay. Last, we will utilize disaggregated or non- disaggregated RA synovial tissues as well as those cultured in a 3D format to determine the effectiveness of blocking the metabolic intermediates activated by the endogenous factor compared to anti-TNF and anti-IL-6R antibodies through phenotyping the metabolic and oxidative signatures and analyzing the tubular formation. The instigators and the mechanism by which glycolytic RA macrophages escalate vascularization & pannus formation is unclear. Hence there is an unmet need to elucidate the mechanism by which endothelial cells adapt to RA macrophage metabolic misfunction to promote pannus hyperplasia in VA patients. The outlined studies will reconceptualize how disconnecting the shared network between RA macrophages and endothelial cells will attenuate pannus in VA patients.