BLRD Research Career Scientist Award Application

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. My laboratory focuses on identifying the mechanisms that lead to joint inflammation, immunometabolism, bone

erosion in immune cells, and their ability to cross-regulate joint vascularization. Our research at Jesse Brown VA Medical Center has focused on discovering a unique TLR7 endogenous ligand in rheumatoid arthritis (RA) synovial fluid exosomes, which exclusively bind to myeloid TLR7. The TLR7 endogenous ligand, miR-Let7b,

remodels the naïve RA myeloid cells into inflammatory MΦs and erosive osteoclasts. Intriguingly, we show that IRAK4 inhibitor therapy disrupts miR-Let7b-mediated inflammatory and metabolic imprints in RA macrophage, fibroblasts, and preclinical models in part via HIF1α and cMYC downregulation. This work is very relevant to the

Veteran's health, as the IRAK4 inhibitor is at phase 2 for RA therapy and could reduce the cost of medical and surgical care and improve the life quality of the veterans. Currently, we aim to identify novel therapeutic targets for patients that do not respond to biotherapies. As such, we have uncovered novel pathways that can markedly alleviate pannus formation by intercepting 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. Intriguingly, we are examining 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. We are also uncovering the impact of the identified synovial fluid endogenous factor on endothelial cell metabolic reprogramming and their cross- regulation with RA macrophages by carbon isotype labeling for tracing glucose, analyzing the structure and

function of mitochondria, and real-time ATP quantification of joint cells. Last, we will utilize RA synovial tissues in 2D or 3D culture format as well as arthritis preclinical models to determine the effectiveness of blocking the metabolic intermediates activated by the identified endogenous factor compared to RA biotherapies through

phenotyping the metabolic and oxidative signatures. In short, the excellent intellectual infrastructure in Jesse Brown Medical Center, combined with the highly productive research team and easy access to RA clinical specimens offers a strong environment for understanding the metabolic crosstalk between RA macrophages and

endothelial cells and the ability to translate the findings from bench-to-bedside.