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.

项目摘要/摘要 骨关节炎（OA）是关节的退化性疾病，在美国60岁以上的人中有16％以上。 年龄和伤害是OA的主要危险因素。迫切需要开发OA的疗法 治疗，因为当前的治疗方案主要依赖于疼痛管理和关节置换，而OA为 仅在我们老龄化的人口中变得越来越普遍。长期暴露于细胞应激源 破坏关节软骨细胞（ACS）的体内平衡，覆盖关节表面的主要细胞类型， 导致关节光滑表面的交流衰老，凋亡和变性。我们知道 对染色质结构的核变化会影响许多组织的生物年龄，并有助于 衰老表型的表现，并希望研究OA中是否也是如此。我们的初步 数据表明，OA中的AC中染色质结构被破坏，可能是OA的一个因素 疾病进展。 该提案的总体目的是剖析衰老和压力如何影响的机制 染色质结构破坏AC稳态以最终引起OA。我们的初步发现暗示 转座元件（TE）的异常激活在OA组织中优先发生。我们假设 这种细胞应力随着年龄的增长而累积，以损害AC中的沉默，从而触发炎症和 最终，OA。我们将测试我们的假设：通过确定染色质访问性和TE激活是否 随着年龄的增长和AC中骨关节炎的存在的增加；通过确定OA模型中的TE激活是否可以 增强OA的进展；并通过评估压力是否引起TE激活和骨关节炎。 影响：该项目将对衰老，压力状况， ERV激活和OA发病机理。重要的是，该提案有可能影响联合健康和 我们老龄化的流动性。