MECHANISM OF DISC PROTEOGLYCAN LOSS IN A MOUSE MODEL OF ACCELERATED AGING

加速衰老小鼠模型中椎间盘蛋白聚糖丢失的机制

• 批准号: 7988883
• 负责人: NAM V VO
• 金额: $ 17.87万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7988883
• 关键词: A Mouse; Age; Age-Months; Age-Years; Aging; Animal Model; Back Pain; Cell Aging; Cell Death; Cell physiology; Cells; Cessation of life; Chronic; DNA Damage; DNA Repair; DNA Repair Endonuclease; Development; Disease; Dose; Economics; Environmental Risk Factor; Etiology; Exposure to; Free Radical Scavengers; Genetic; Genotoxic Stress; Injury; Intervertebral disc structure; Ionizing radiation; Low Back Pain; Measures; Mechanics; Mediator of activation protein; Molecular; Mus; Oxidative Stress; Play; Proteoglycan; Radiation; Role; Smoke; Smoking; Source; Spinal; Spinal Stenosis; Testing; Therapeutic Intervention; United States; Vertebral column; age related; disability; effective therapy; functional loss; insight; intervertebral disk degeneration; ionization; mouse model; novel; oxidative DNA damage; prevent; public health relevance; research study; spine bone structure

DESCRIPTION (provided by applicant): Intervertebral disc degeneration (IDD) contributes to many spinal disorders such as chronic disabling low back pain, disc herniation, spinal stenosis and vertebral instability. IDD-associated back pain is the leading source of disability in people 45 years of age or younger, resulting in national economic losses estimated at more than 90 billion dollars a year in the United State alone. IDD is correlated with many diverse pathophysiologic etiologies, including genetics, smoking, mechanical injury, aging and other environmental factors, with aging being an inevitable and key contributor of IDD. Oxidative stress and genotoxic stress are widely accepted to contribute to aging in general10. However, whether oxidative or genotoxic stress are also a key culprits in disc aging has not been adequately explored due to a lack of a good animal model of age-related IDD. We recently demonstrated that a mouse model of accelerated aging (Ercc1-/ mice) caused by reduced expression of the DNA repair endonuclease ERCC1-XPF displays considerable disc matrix proteoglycan (PG) loss, a universal hallmark of disc aging, by five months of age. This leads us to hypothesize that accumulation of endogenous DNA damage plays a causal role in disc aging and PG loss. To test this hypothesis, two aims are proposed: (1) to determine if IDD is due to oxidative/genotoxic stress-induced disc cell senescence and death and loss of cell function, and (2) to determine if oxidative/genotoxic stress induces disc matrix PG degradation. The successful completion of these experiments will determine if there is a causal relationship between oxidative DNA damage and age- associated IDD and yield novel insights into the molecular causes of disc PG loss that will be useful for development of rational therapeutic interventions to prevent or delay IDD. PUBLIC HEALTH RELEVANCE: These studies aim at understanding how aging intervertebral discs lose important matrix structural constituents in order to develop rational and effective treatment of spinal disorders such as chronic disabling low back pain.

描述(申请人提供)：椎间盘退行性变(IDD)导致许多脊柱疾病，如慢性致残性下腰痛、椎间盘突出、椎管狭窄和椎体不稳。与IDD相关的背痛是45岁或以下人群残疾的主要来源，仅在美国每年造成的国家经济损失估计就超过900亿美元。IDD与多种病理生理因素有关，包括遗传、吸烟、机械损伤、衰老和其他环境因素，其中衰老是IDD不可避免的关键因素。人们普遍认为，氧化应激和基因毒性应激是导致衰老的主要原因。然而，由于缺乏良好的老年性IDD动物模型，氧化应激或遗传毒性应激是否也是椎间盘老化的主要原因尚未得到充分的研究。我们最近证明，由DNA修复内切酶ERCC1-XPF表达减少引起的加速衰老(ERCC1-/小鼠)小鼠在5个月大时表现出大量的盘基质蛋白多糖(PG)丢失，这是椎间盘老化的普遍标志。这导致我们假设，内源性DNA损伤的积累在椎间盘老化和PG丢失中起着因果作用。为了验证这一假说，提出了两个目标：(1)确定IDD是否是由于氧化/遗传毒性应激诱导的椎间盘细胞衰老、死亡和细胞功能丧失所致；(2)确定氧化/遗传毒性应激是否诱导椎间盘基质PG降解。这些实验的成功完成将确定氧化DNA损伤与年龄相关性IDD之间是否存在因果关系，并对椎间盘PG丢失的分子原因提供新的见解，这将有助于开发合理的治疗干预措施来预防或延迟IDD。 公共卫生相关性：这些研究旨在了解老化的椎间盘如何失去重要的基质结构成分，以便开发合理和有效的脊柱疾病治疗方法，如慢性致残下腰痛。