Epigenetic Regulation of Phlpp1 in Cartilage Development and Regeneration

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DESCRIPTION (provided by applicant): Abstract Osteoarthritis (OA) is the most common form of arthritis and a leading cause of disability in older Americans; thus, OA poses an enormous social and economic burden in the US. OA progression is certain and since cartilage has limited regenerative capacity, total joint replacement is the only effective treatment for OA. Despite the high success rates of reducing pain and restoring mobility, joint implants have limited lifespans and surgeries present many risks, including infections. Thus, new strategies to promote articular cartilage repair and/or slow articular cartilage degeneration and disease progression are needed. The goal of this five year career development application is to establish a research program exploring the role of the protein phosphatase Phlpp1 in osteoarthritis disease (OA) progression and to explore the epigenetic mechanisms that control Phlpp1 transcription in OA. To date, the applicant's research experience focused mainly on cellular and genetic models that do not recapitulate the OA phenotype. The proposed research in this application will further advance the investigator's qualifications by providing training in surgical models of osteoarthriti and their characterization through functional assessments of pain, equilibrium partitioning of an ionic contrast agent via microcomputed tomography (EPIC-microCT), histological scoring and epigenetic/transcriptional control of gene expression. This training will provide a comprehensive skill set required for mechanistic studies detailing the ability of epigenetic factors to modulate OA progression. The completion of this project and the training received at the Mayo Clinic will prepare the Principal Investigator to be a leading contributor to the field of osteoarthritis-relatd research.