Mediators of the OA Cascade in the Pre-Arthritic Hip

项目摘要 博士Cecilia Pascual-Garrido，医学博士，博士是一名髋关节保留和成人重建外科医生，其研究 目标是为患有OA前髋关节疾病的年轻人的护理做出重大和有意义的贡献， 通过基础科学发现及其转化为病人护理的过程。她的教育，临床和 研究经验使她为从事这项工作做好了独特的准备，而这项职业发展奖将有助于 她所需要的补充性肌肉骨骼研究培训，重点是表观遗传学， 转录组、生物信息学和统计学概念。所有活动都将在华盛顿大学学院举行 该机构拥有强大的健康服务研究计划和肌肉骨骼研究小组。 最近的报告表明，在高达50%的OA病例中，股骨髋臼撞击（FAI）是一种病因。超过 美国每年有30万人接受初次全髋关节置换术（THR）， 预计到2030年将翻一番。虽然FAI中髋骨畸形的特征已被广泛研究， 关节内炎症和表观遗传变化在这种疾病中的作用尚不清楚。为了解决这个 需要，本项目的目的是确定关键的生物学事件，这些事件是髋关节OA级联反应的介质 阿辉目的1将确定髋关节FAI撞击区关节软骨细胞（AC）的分解代谢状态。 FAI（早期）和OA（晚期）中撞击区的AC将在含有TGF β 1和TGF β 2的培养物中进行测试。 IL-1 β我们希望能够描述病理细胞中的分解代谢状态和异常DNA甲基化。目标2将 通过基因表达和DNA甲基化谱表征疾病谱（正常FAI和OA） 基于.我们的初步数据显示，与FAI相比，髋关节OA的生物学过程丰富。另外我们 将研究髋关节OA和髋关节FAI的全基因组甲基化谱。我们相信，整合 表观基因组和转录组数据将使我们能够更好地了解所确定的基因座如何有助于 OA发病机制。ATAC-seq在OA中的应用是新颖的，并且可能具有巨大的临床意义， 确定可能参与髋关节OA发病机制的启动子和增强子基因的改变。最后， 目的3将描述髋关节FAI和继发性OA的小动物模型。这种动物模型可以提供一种 这是检验未来髋关节OA治疗的介入研究的新机会。通过既定 与我们机构的肌肉骨骼研究人员和临床科学家合作，该应用程序具有 有可能发现与髋关节OA继发于髋关节FAI相关的早期病理通路， 重要的诊断和临床意义。

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.