PROJECT ABSTRACT Dr. Cecilia Pascual-Garrido, MD, PhD is a hip preservation and adult reconstruction surgeon whose research goal is to make significant and meaningful contributions in the care of young adults with pre-OA hip disorders, through the process of basic scientific discovery and its translation to patient care. Her educational, clinical and research experiences uniquely prepare her to pursue this work, and this career development award will facilitate the complementary musculoskeletal research training she requires, with an emphasis on epigenetics, transcriptome, bioinformatics and statistical concepts. All activities will occur at the Washington University School of Medicine, an institution with strong health services research program and musculoskeletal research group. Recent reports indicate an etiologic role of Femoroacetabular Impingement (FAI) in up to 50% of OA cases. Over 300,000 individuals in the US undergo primary total hip replacement (THR) annually, with THR utilization projected to double by 2030. While characterization of hip bone deformity in FAI has been extensively studied, the role of intraarticular inflammation and epigenetic changes plays in this disease is unknown. To address this need, the purpose of this project is to identify critical biologic events that are mediators of the OA cascade in hip FAI. Aim 1 will identify a catabolic state in articular chondrocytes (ACs) from the impingement zone in hip FAI. ACs from the impingement zone in FAI (early stage) and OA (late stage) will be tested in cultures with TGF and IL-1. We hope to characterize a catabolic state and abnormal DNA methylation in pathological cells. Aim 2 will characterize spectrum of disease (normal-FAI and OA) through gene expression and DNA methylation profile based. Our preliminary data shows enriched biological processes in hip OA compared to FAI. Additionally, we will investigate that genome-wide methylation profiling in hip OA and hip FAI. We believe that integrating epigenomic and transcriptome data will allow us to better understand how the identified loci may contribute to OA pathogenesis. The application of ATAC-seq in OA is novel and could have tremendous clinical implication to identify altered promoters and enhancer genes that might be involved in the pathogenesis of hip OA. Finally, Aim 3 will characterize a small animal model of hip FAI and secondary OA. This animal model could provide a novel opportunity to test future interventional studies for the treatment of hip OA. Through established collaboration with musculoskeletal researchers and clinician scientists in our institution, this application has the potential to uncover early pathological pathways associated with hip OA secondary to hip FAI, which may have important diagnostic and clinical implications.