PROJECT SUMMARY/ABSTRACT Osteoarthritis (OA) is the most prevalent joint disease and a leading cause of mobility related disability in the United States. Post-traumatic OA (PTOA), OA developed after injury, has been recognized as a significant etiology and subtype of OA and accounts for approximately 12% of all cases of symptomatic OA. There is a pressing and unmet clinical need of developing novel prevention and treatment strategies of PTOA in this young and active patient population. ACL injury is a proven high-risk factor for PTOA development despite ACL reconstruction (ACLR). The parent study proposed to investigate 200+ patients after ACLR from the unique, NIH-funded, and well characterized nested cohort of the Multicenter Orthopaedic Outcomes Network (MOON) (termed as MOON Onsite Cohort). The parent study aims to characterize long-term structural damage 10 years after ACLR using novel quantitative MRI (qMRI), understand their relationship to patient outcomes, and identify modifiable predictors for PTOA from early time points. In this competing revision, we aim to expand the parent study by recruiting the final 100+ patients from the same MOON Onsite Cohort, to develop and apply novel PTOA radiomics to the entire cohort, and to explore neural mechanisms of pain in PTOA with brain MRI. Pain is the major factor that significantly impairs quality of life of OA patients. However, our understanding of pain in OA is very limited. A better understanding of the pain mechanisms and identifying biomarkers that associate or predict pain will be critical for improving patient management and designing novel treatment strategies in OA. Several structural factors, in particular bone marrow edema-like lesions and synovitis, have been correlated to pain in knee OA. However, these studies were normally performed in cohorts with primary OA. The relationship between imaging features and pain in younger patients with PTOA is largely unknown. Furthermore, although traditionally OA is considered purely ‘nociceptive’, increasing evidence have suggested ‘neuropathic-like pain’ in OA. Previous neuro-imaging studies have demonstrated both structural and functional changes in brains of patients with OA pain. Despite the promising results, the investigation of the neural mechanism of OA pain is in its infancy, and no studies have yet explored the neural mechanism of PTOA pain. The proposed study was designed with long-term goals to fill these gaps. Our overarching goal is to better understand structural and symptomatic PTOA development, to explore pain mechanisms in PTOA, and to identify potential imaging markers that associate and predict pain in PTOA. The proposed study will leverage the NIH-funded, well characterized MOON cohort, and the established platforms of multisite qMRI with rigorous quality control from the parent study. Combining the parent and proposed study, we will build a highly unique PTOA cohort with comprehensive measures, including advanced imagin...