Mediators of the OA Cascade in the Pre-Arthritic Hip

关节炎前髋部 OA 级联的调节者

基本信息

批准号：
10254394
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
项目类别：
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/10254394
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

项目摘要

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、哲学博士是一位髋关节保留和成人重建外科医生，她的研究目标是为患有 OA 前髋部疾病的年轻人的护理做出重大且有意义的贡献，通过基本科学发现及其转化为患者护理的过程。研究经历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，所有活动都将在华盛顿大学学院进行。医学学院，一个拥有强大的健康服务研究项目和肌肉骨骼研究小组的机构。最近的报告表明股髋臼撞击 (FAI) 在高达 50% 的 OA 病例中起着病因作用。美国每年有 300,000 人接受初次全髋关节置换术 (THR)，THR 的利用预计到 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。需要，该项目的目的是确定髋关节 OA 级联介导的关键生物事件 FAI。目标 1 将识别髋部 FAI 撞击区的关节软骨细胞 (AC) 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 TGF 的培养物中进行测试 IL-1。我们希望能够表征病理细胞中的分解代谢状态和异常 DNA 甲基化。通过基因表达和 DNA 甲基化谱表征疾病谱（正常 FAI 和 OA）我们的初步数据显示，与 FAI 相比，髋关节 OA 的生物过程更加丰富。我们将研究髋关节 OA 和髋关节 FAI 中的全基因组甲基化分析。表观基因组和转录组数据将使我们能够更好地了解已识别的基因座如何有助于 ATAC-seq 在 OA 发病机制中的应用是新颖的，可能具有巨大的临床意义。鉴定可能参与髋关节 OA 发病机制的改变的启动子和增强子基因。目标 3 将描述髋部 FAI 和继发性 OA 的小动物模型，该动物模型可以提供一个模型。通过已建立的方法来测试未来治疗髋关节 OA 的介入研究的新机会。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揭示继发于髋关节 FAI 的髋关节 OA 相关的早期病理通路，这可能有重要的诊断和临床意义。