Epigenetic Regulation of Phlpp1 in Cartilage Development and Regeneration

描述（由申请人提供）：摘要骨关节炎（OA）是关节炎的最常见形式，也是美国老年人残疾的主要原因;因此，OA在美国造成了巨大的社会和经济负担。骨关节炎的进展是肯定的，由于软骨的再生能力有限，全关节置换术是唯一有效的治疗骨关节炎。尽管减轻疼痛和恢复活动能力的成功率很高，但关节植入物的寿命有限，而且手术存在许多风险，包括感染。因此，需要促进关节软骨修复和/或减缓关节软骨退化和疾病进展的新策略。这个为期五年的职业发展申请的目标是建立一个研究计划，探索蛋白磷酸酶Phlpp 1在骨关节炎疾病（OA）进展中的作用，并探索控制Phlpp 1转录的表观遗传机制。迄今为止，申请人的研究经验主要集中在不概括OA表型的细胞和遗传模型上。本申请中的拟议研究将通过提供骨关节炎手术模型及其表征方面的培训来进一步提高研究者的资格，这些培训通过疼痛的功能评估、离子造影剂通过微计算机断层扫描（EPIC-microCT）的平衡分配、组织学评分和基因表达的表观遗传/转录控制进行。该培训将提供详细说明表观遗传因素调节OA进展的能力的机制研究所需的全面技能。该项目的完成和在马约诊所接受的培训将使主要研究者成为骨关节炎相关研究领域的主要贡献者。

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.