Mediators of the OA Cascade in the Pre-Arthritic Hip

关节炎前髋部 OA 级联的调节者

• 批准号: 10039772
• 负责人: Cecilia Pascual-Garrido
• 金额: $ 15.57万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-04 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10039772
• 关键词: ADAMTS; ATAC-seq; Address; Adult; Amino Acids; Animal Model; Antibodies; Arthritis; Attenuated; Bioinformatics; Biological; Biological Process; Cadaver; Caring; Cartilage; Cells; Chondrocytes; Chromatin; Clinical; Clinical Research; Collaborations; CpG Islands; DNA; DNA Methylation; DNMT3B gene; Data; Deformity; Development; Diagnostic; Disease; Disease Progression; Doctor of Philosophy; Enhancers; Epigenetic Process; Etiology; Event; Future; Gene Expression; Genes; Goals; Head; Health Services Research; Hip Joint; Hip Osteoarthritis; Hip region structure; Homeostasis; Human; Immune response; Individual; Inflammation; Inflammatory; Injury; Institution; Interleukin-1; Interleukin-1 beta; Intervention Studies; K-Series Research Career Programs; Knee Osteoarthritis; Knowledge; Medial; Mediator of activation protein; Methylation; Modeling; Molecular; Mus; Musculoskeletal; NF-kappa B; Operative Surgical Procedures; Oryctolagus cuniculus; Pathogenesis; Pathologic; Pathway interactions; Patient Care; Patient Outcomes Assessments; Patients; Phenotype; Play; Process; Reporting; Research; Research Personnel; Research Project Grants; Research Training; Role; Sampling; Scientist; Secondary to; Signal Transduction; Stains; Surgeon; Testing; Therapeutic Intervention; Total Hip Replacement; Transcript; Transferase; Translations; Universities; Washington; Western Blotting; Work; articular cartilage; base; bone; chromatin immunoprecipitation; collagenase 3; epigenomics; experience; follow-up; gamma-Aminobutyric Acid; genome wide methylation; hip bone; improved; loss of function; medical schools; neutrophil; novel; preservation; programs; promoter; reconstruction; skills; transcriptome; transcriptome sequencing; young adult

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.

项目摘要 塞西莉亚·帕斯夸尔·加里多博士是一名髋关节保存和成人重建外科医生，她的研究 目标是在护理患有骨性关节炎前髋关节紊乱的年轻人方面做出重大而有意义的贡献， 通过基础科学发现的过程并将其转化为病人护理。她的教育，临床和 研究经验为她从事这项工作做好了独特的准备，而这个职业发展奖将促进 她需要补充肌肉骨骼研究培训，重点是表观遗传学， 转录组、生物信息学和统计学概念。所有活动将在华盛顿大学学校举行 拥有强大的医疗服务研究计划和肌肉骨骼研究小组的机构。 最近的报告表明，髋臼撞击(FAI)在高达50%的OA病例中起到了病因学作用。完毕 美国每年有30万人接受初次全髋关节置换术(THR)，并利用THR 预计到2030年将翻一番。虽然FAI的髋骨畸形的特征已经被广泛研究， 关节内炎症和表观遗传学改变在这种疾病中所起的作用尚不清楚。要解决这个问题 需要，这个项目的目的是确定关键的生物事件是髋关节骨关节炎级联反应的媒介 阿辉。目的1鉴定髋关节FAI撞击区关节软骨细胞的分解代谢状态。 来自FAI(早期)和OA(晚期)撞击区的AC将在含有转化生长因子和 IL-1。我们希望描述病理细胞的分解代谢状态和异常的DNA甲基化。目标2将 通过基因表达和DNA甲基化图谱表征疾病谱(正常-FAI和OA) 基于。我们的初步数据显示，与FAI相比，髋关节骨关节炎具有丰富的生物学过程。此外，我们 将调查髋关节骨性关节炎和髋关节FAI的全基因组甲基化图谱。我们相信，整合 表观基因组和转录组数据将使我们更好地理解已识别的基因座如何对 骨性关节炎发病机制。ATAC-seq在骨性关节炎中的应用是新的，并可能具有巨大的临床意义。 确定改变的启动子和增强子基因，可能参与髋关节骨性关节炎的发病机制。最后， 目的3将表征一个小动物模型的髋关节FAI和继发性骨关节炎。这种动物模型可以提供一种 测试未来治疗髋关节骨性关节炎的介入研究的新机会。通过建立 与我们机构的肌肉骨骼研究人员和临床科学家合作，这个应用程序具有 有可能发现继发于髋关节FAI的髋关节骨性关节炎的早期病理途径，这可能是 重要的诊断和临床意义。