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（由申请人提供）：椎间盘椎间盘退化（IDD）有助于许多脊髓疾病，例如慢性残疾腰痛，椎间盘突出症，脊柱狭窄和椎骨不稳定。与IDD相关的背痛是45岁以下人群中残疾的主要来源，仅在美国，每年估计每年超过900亿美元的国家经济损失。 IDD与许多不同的病理生理病因相关，包括遗传学，吸烟，机械损伤，衰老和其他环境因素，而衰老是IDD的不可避免和关键因素。氧化应激和遗传毒性应激被广泛接受，可导致一般衰老10。但是，由于缺乏与年龄相关的IDD的良好动物模型，氧化性或遗传毒性应激也是椎间盘衰老中的关键罪魁祸首。我们最近证明，由DNA修复核酸内切酶ERCC1-XPF的表达降低引起的加速衰老（ERCC1-/小鼠）的小鼠模型显示出相当大的椎间盘基质蛋白聚糖蛋白聚糖（PG）损失，这是椎间盘老化的通用标志，年龄五个月。这使我们假设内源性DNA损伤的积累在椎间盘衰老和PG损失中起因果作用。为了检验这一假设，提出了两个目的：（1）确定IDD是否是由于氧化/遗传毒性应激诱导的椎间盘衰老，死亡和细胞功能的丧失，以及（2）确定氧化/遗传毒性应激是否诱导椎间盘基质降解。这些实验的成功完成将确定氧化性DNA损伤与年龄相关的IDD之间是否存在因果关系，并产生对椎间盘PG损失的分子原因的新颖见解，这将有助于开发有理学治疗干预措施，以预防或延迟IDD。 公共卫生相关性：这些研究旨在了解衰老的椎间盘如何失去重要的矩阵结构成分，以便开发出对脊柱疾病（例如慢性残疾下背部疼痛）的合理有效治疗。