Endogenous retrovirus in joint aging and osteoarthritis development

内源性逆转录病毒在关节衰老和骨关节炎发展中的作用

• 批准号: 10719364
• 负责人: Ting Wang
• 金额: $ 60.78万
• 依托单位: VAN ANDEL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10719364
• 关键词: ATAC-seq; Acceleration; Adult; Affect; Age; Aging; Apoptosis; Biological; Biological Models; Cartilage; Cells; Cellular Stress; ChIP-seq; Chondrocytes; Chromatin; Chromatin Structure; Chronic; Clinical; DNA Methylation; DNA Transposable Elements; Data; Degenerative Disorder; Degenerative polyarthritis; Deposition; Development; Disease; Disease Progression; Double-Stranded RNA; Endogenous Retroviruses; Enhancers; Epigenetic Process; Exposure to; Gene Expression; Genes; Genetic Transcription; Genome; Health; Heterochromatin; Histones; Homeostasis; Human; Impairment; Inflammation; Inflammatory; Injury; Joints; Knock-out; Knockout Mice; Mechanics; Mediating; Medical; Methylation; Modeling; Mus; Neurodegenerative Disorders; Nuclear; Pain management; Pathogenesis; Pattern; Persons; Phenotype; Prevention; Recording of previous events; Replacement Arthroplasty; Research; Risk Factors; Role; SETDB1 gene; Sampling; Scientific Advances and Accomplishments; Societies; Stress; Surface; Testing; Tissues; Transcript; Transcriptional Silencer Elements; Viral; Wild Type Mouse; Work; age related; aging population; cell type; defense response; empowerment; epigenome; experimental study; healing; inflammatory marker; interest; overexpression; oxidation; postmitotic; premature; prevent; promoter; self-renewal; senescence; stressor; therapy development; transcriptome; transcriptome sequencing; transcriptomics; translational potential

Project Summary/Abstract Osteoarthritis (OA) is a degenerative disease of the joints, that affects over 16% of people over 60 in the US. Age and injury are the primary risk factors for OA. There is a critical need to develop therapies for OA treatment, as current treatment options rely primarily on pain management and joint replacement, while OA is only becoming increasingly prevalent in our aging population. Chronic exposure to cellular stressors profoundly disrupts the homeostasis of articular chondrocytes (ACs), the primary cell type covering the surface of the joint, leading to AC senescence, apoptosis, and degeneration of the smooth surface of the joint. We know that nuclear changes to chromatin structure impacts the biological age of many tissues and contributes to the manifestation of aging phenotypes and wanted to investigate whether this is also true in OA. Our preliminary data suggests that chromatin structure is disrupted in ACs in OA and may be a contributing factor to OA disease progression. The overall objective of this proposal is to dissect the mechanism(s) of how aging and stressors influence chromatin structure to disrupt AC homeostasis to ultimately give rise to OA. Our preliminary findings suggest that abnormal activation of transposable elements (TEs) occurs preferentially in OA tissue. We hypothesize that cellular stresses accumulate with age to impair TE silencing in ACs, thereby triggering inflammation and eventually, OA. We will test our hypothesis: by determining if chromatin accessibility and TE activation increase with age and presence of osteoarthritis in ACs; by determining if TE activation in OA models can augment OA progression; and by evaluating if stress causes TE activation and osteoarthritis. Impact: This project will yield a mechanistic understanding of the connection between aging, stress conditions, ERV activation, and OA pathogenesis. Importantly, this proposal has the potential to impact joint health and mobility of our aging population.

项目概要/摘要 骨关节炎 (OA) 是一种关节退行性疾病，影响美国 60 岁以上人群中超过 16% 的患者。 年龄和损伤是 OA 的主要危险因素。迫切需要开发 OA 疗法 治疗，因为目前的治疗选择主要依赖于疼痛管理和关节置换，而 OA 在我们的老龄化人口中只会变得越来越普遍。长期暴露于细胞应激源 破坏关节软骨细胞（AC）的稳态，这是覆盖关节表面的主要细胞类型， 导致AC衰老、细胞凋亡和关节光滑表面的退化。我们知道 染色质结构的核变化影响许多组织的生物年龄，并有助于 衰老表型的表现，并想研究 OA 中是否也存在这种情况。我们的初步 数据表明 OA 中 AC 的染色质结构被破坏，可能是 OA 的一个促成因素 疾病进展。 该提案的总体目标是剖析衰老和压力源如何影响的机制 染色质结构破坏 AC 稳态，最终导致 OA。我们的初步研究结果表明 转座因子（TE）的异常激活优先发生在 OA 组织中。我们假设 细胞压力随着年龄的增长而积累，损害 AC 中的 TE 沉默，从而引发炎症和 最终，OA。我们将测试我们的假设：通过确定染色质可及性和 TE 激活是否 随着年龄的增长和 AC 中骨关节炎的存在而增加；通过确定 OA 模型中的 TE 激活是否可以 促进 OA 进展；并评估压力是否会导致 TE 激活和骨关节炎。 影响：该项目将对衰老、压力条件、 ERV 激活和 OA 发病机制。重要的是，该提案有可能影响关节健康和 老龄化人口的流动性。