PROJECT SUMMARY Osteoarthritis (OA) is a progressive and degenerative joint disease with an increasing prevalence in the aging population for which existing treatments targeting the primary symptom of pain are only minimally successful. The manifestation of OA is heterogeneous with symptomology differing across individuals. This disease heterogeneity has made identification of reliable and consistent molecular biomarkers elusive. This has in part hindered the progress toward development of specific therapeutic treatments. Therefore, the identification of specific biomarkers of OA clinical phenotypes and longitudinal changes over disease progression is required. To begin addressing this issue, here we propose an initiative for the discovery of plasma extracellular RNA (exRNA) expression signatures genomic signatures of OA among diverse clinical and progressive phenotypes. exRNA has been demonstrated in a variety of complex diseases to have prognostic and biological value. The experiments will utilize the Osteoarthritis Initiative (OAI) which is a prospective, longitudinal multicenter cohort study of nearly 5000 subjects diagnosed with radiographic knee OA or at risk for the disease. We will first cluster the entire OAI cohort into distinct clinical phenotypes based on biochemical assays, imaging data, and clinical symptom questionnaires and identify exRNA signatures associated with those phenotypes using high throughput RNA sequencing (SA1). Furthermore, we will identify individuals with progressive OA defined as progression by radiograph changes over time as well as increasing pain over time. We will then generate longitudinal time- course profiles of exRNA expression to deduce biological mechanisms of that progression (SA2). By generating specific phenotype definitions, this study has increased power to identify molecular signatures of these OA groups. This will be an important step toward harnessing the value of functional genomics as a biomarker in the precision medicine of OA.