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 Cecilia Pascual-Garrido博士，医学博士，博士是髋关节保存和成人重建外科医生的研究 目标是在患有前OA髋关节疾病的年轻人的护理中做出重大而有意义的贡献， 通过基本科学发现的过程及其转化为患者护理。她的教育，临床和 研究经验独特地为她做好准备从事这项工作，这项职业发展奖将准备 她需要的完整肌肉骨骼研究培训，重点是表观遗传学 转录组，生物信息学和统计概念。所有活动将在华盛顿大学学校举行 医学，具有强大卫生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，股骨替代撞击（FAI）在多达50％的OA病例中的病因作用。超过 美国300,000个人每年进行主要的总髋关节置换（THR），并使用THR利用率 预计到2030年将两倍。 关节内炎症和表观遗传变化在该疾病中的作用尚不清楚。解决这个问题 需求，该项目的目的是确定关键的生物学事件，这些事件是HIP中OA级联的介体 fai。 AIM 1将在髋关节撞击区域中识别关节软骨细胞（AC）中的分解代谢状态。 FAI（早期）和OA（晚期）的撞击区的AC将在TGF和TGF和 IL-1。我们希望表征病理细胞中的分解代谢状态和异常DNA甲基化。 AIM 2意志 通过基因表达和DNA甲基化谱图表征疾病光谱（正常-FAI和OA） 基于。我们的初步数据显示，与FAI相比，髋关节OA中的生物学过程富集。另外，我们 将研究髋关节和髋关节FAI中的全基因组甲基化分析。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鉴定的本地如何有助于 OA发病机理。 ATAC-SEQ在OA中的应用是新颖的，可能对 确定可能参与髋关节发病机理的启动子和增强子基因。最后， AIM 3将表征髋关节和次级OA的小动物模型。这种动物模型可以提供 测试未来介入研究以治疗髋关节OA的新机会。通过建立 与我们机构中的肌肉骨骼研究人员和临床科学家合作，该应用具有 潜在发现与髋关节继发的髋关节OA相关的早期病理途径，这可能具有 重要的诊断和临床意义。