Systemic contribution of age-associated epigenetic mechanisms to osteoarthritis

年龄相关表观遗传机制对骨关节炎的系统性贡献

基本信息

批准号：
10465071
负责人：
Michelle Szu-Huei Yau
金额：
$ 42.55万
依托单位：
HEBREW REHABILITATION CENTER FOR AGED
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-09 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10465071
关键词：
Acceleration Affect Age Aging Ancillary Study Arthritis Biological Biological Aging Blood Cells Chondrocytes Chronology Cluster Analysis Code Communities Complement CpG dinucleotide Cytosine DNA Methylation DNA Sequence Data Degenerative polyarthritis Disease Disease Progression Enhancers Environmental Risk Factor Epigenetic Process Exhibits Future Gene Expression Genes Genetic Risk Genetic study Genomics Goals Growth Factor Hand Hand Osteoarthritis Hip region structure Image Immune Incidence Individual Inflammaging Inflammation Mediators Joints Knee Knee Osteoarthritis Measures Medical Methylation Modification Molecular Obesity Outcome Pain Parents Participant Pathogenesis Pathway Analysis Pathway interactions Persons Pharmacological Treatment Pharmacotherapy Phenotype Process Proteomics Public Health Quality of life Research Risk Risk Factors Role Site Smoking Stress Synovial joint Time Tissues Treatment Cost United States Visit Work age related aging population bead chip burden of illness cohort cost disabling disease drug development epigenetic marker epigenome epigenome-wide association studies genome-wide insight joint injury joint loading loss of function metabolomics novel novel marker physically handicapped protein expression radiological imaging response targeted biomarker targeted therapy trials transcriptomics treatment strategy

项目摘要

PROJECT SUMMARY Osteoarthritis (OA) is the most common form of arthritis in the United States and a leading cause of physical disability in older individuals. There are no approved pharmacologic treatments available beyond those for symptomatic relief. Thus, identifying new treatment targets is critical to reducing the burden of OA. While age is one of the strongest predictors of OA, the disease mechanisms that underlie the relationship between cellular and molecular hallmarks of aging and OA are unclear. The long-term goal of this ancillary study is to identify potential new targets for OA therapy by identifying key age-associated biological mechanisms underlying OA pathogenesis. The objective of this project is to determine the role of epigenetic changes to genes in key aging pathways on OA. The central hypothesis is that aging is associated with epigenetic modifications affecting DNA methylation levels in immune blood cells (i.e., `inflammaging') and will be associated with greater burden of disease across commonly affected synovial joints, including the hands, knees and hips. Epigenetic modifications that affect downstream changes in gene and protein expression without altering the DNA sequence may provide important insights into OA pathogenesis that are not captured by information on genetic or environmental risk factors. The contribution of age-related epigenetic mechanisms to OA burden will be assessed in the MOST study, an ongoing well-characterized cohort of individuals with and without early stage knee OA. The pending reexamination of MOST subjects presents a unique, time-sensitive opportunity to obtain contemporaneous measures of epigenetic markers and OA burden that includes assessments of hand OA from radiographs. New acquisition of hand radiographs will be combined with the ongoing radiographic imaging of knees and hips to constitute a multiple joint OA phenotype. The acquisition of hand radiographs and genome-wide DNA methylation will make it possible for the first time in MOST to study the relation of epigenetic factors with multiple joint OA. Aims of the study include 1) determining whether epigenetic age acceleration is associated with multiple joint OA by assessing the difference between chronological age and epigenetic molecular age, then relating this to multiple joint OA and 2) identifying novel epigenetic markers associated with multiple joint OA by performing an epigenome-wide association study, then pathway analyses and hierarchical clustering to identify whether differentially methylated loci and OA subtypes are enriched for biological pathways related to aging. The expected outcome is identification of age-associated epigenetic mechanisms that underlie OA pathogenesis, which is needed to identify relevant OA treatment targets and biomarkers that could be used to identify at-risk individuals earlier in the disease process before the onset of structural changes in the joint. The proposed ancillary study will also provide valuable epigenetics data that will lay the groundwork for future integrative studies of genetics/genomics in the MOST parent study, greatly enhancing its scientific value to the medical community.

项目摘要骨关节炎（OA）是美国最常见的关节炎形式，也是物理的主要原因老年人的残疾。除批准的药理治疗外有症状的缓解。因此，确定新的治疗靶标对于减轻OA的负担至关重要。年龄是OA的最强预测因素之一，该疾病机制是基于衰老和OA的细胞和分子标志尚不清楚。这项辅助研究的长期目标是通过识别关键年龄相关的生物学机制来确定OA治疗的潜在新靶基础OA发病机理。该项目的目的是确定表观遗传变化对 OA关键老化途径中的基因。中心假设是衰老与表观遗传学有关影响免疫细胞中DNA甲基化水平的修饰（即“炎症”），将为与常见的滑膜关节（包括手）中的疾病负担更大有关膝盖和臀部。影响基因和蛋白质表达下游变化的表观遗传修饰如果不改变DNA序列，可能会为未捕获的OA发病机理提供重要的见解通过有关遗传或环境风险因素的信息。与年龄相关的表观遗传学的贡献在最多的研究中，将评估oa负担的机制有和没有早期膝盖OA的人。大多数主题的即将进行的重新审查提出了独特的，时间敏感的机会，以获得同时的表观遗传标记和OA负担这包括对X光片的手室OA的评估。手动X光片的新收购将是结合膝盖和臀部的持续放射线照相成像，构成了多个关节OA表型。手动X光片和全基因组DNA甲基化的获取将首次成为可能大多数人研究表观遗传因子与多个关节OA的关系。研究的目的包括1）通过评估表观遗传年龄加速度是否与多个关节OA相关年代年龄和表观遗传分子年龄之间的差异，然后将其与多个关节OA和 2）通过执行表观基因组识别与多个关节OA相关的新型表观遗传标记协会研究，然后进行途径分析和分层聚类，以识别是否差异化甲基化的基因座和OA亚型富含与衰老有关的生物学途径。预期的结果是鉴定与OA发病机理的年龄相关的表观遗传机制，这是必需的确定可用于较早识别高危个人的相关OA治疗目标和生物标志物关节结构变化开始之前的疾病过程。拟议的辅助研究也将提供有价值的表观遗传学数据，将为将来的综合研究奠定基础在最父母的研究中，遗传学/基因组学大大增强了其对医学界的科学价值。