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: 8128658
• 负责人: NAM V VO
• 金额: $ 14.93万
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8128658
• 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; ERCC1 gene; 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; Modeling; Molecular; Mus; Oxidative Stress; Play; Proteoglycan; Radiation; Role; 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）：椎间盘退变（IDD）可导致许多脊柱疾病，如慢性致残性腰痛、椎间盘突出、椎管狭窄和椎体不稳定。与IDD相关的背痛是45岁或以下人群残疾的主要原因，仅在美国，每年造成的国家经济损失估计超过900亿美元。IDD与许多不同的病理生理学病因相关，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。氧化应激和遗传毒性应激被广泛认为是导致衰老的原因10。然而，由于缺乏与年龄相关的IDD的良好动物模型，氧化或遗传毒性应激是否也是椎间盘老化的关键因素尚未得到充分研究。我们最近证明，由DNA修复核酸内切酶ERCC 1-XPF的表达减少引起的加速老化的小鼠模型（Ercc 1-/小鼠）显示出相当大的椎间盘基质蛋白聚糖（PG）损失，这是5个月龄时椎间盘老化的普遍标志。这使我们假设内源性DNA损伤的积累在椎间盘老化和PG丢失中起因果作用。为了检验这一假设，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和死亡以及细胞功能丧失，以及（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性DNA损伤和年龄相关IDD之间是否存在因果关系，并产生对椎间盘PG丢失的分子原因的新见解，这将有助于开发合理的治疗干预措施以预防或延迟IDD。 公共卫生相关性：这些研究旨在了解老化的椎间盘如何失去重要的基质结构成分，以开发合理有效的治疗脊柱疾病，如慢性致残性腰痛。

项目成果

Prostaglandin E2 and prostaglandin F2α differentially modulate matrix metabolism of human nucleus pulposus cells.

• DOI: 10.1002/jor.21157
• 发表时间: 2010-10
• 期刊: Journal of orthopaedic research : official publication of the Orthopaedic Research Society
• 作者: Vo NV;Sowa GA;Kang JD;Seidel C;Studer RK
• 通讯作者: Studer RK

Functional probe for annulus fibrosus-targeted intervertebral disc degeneration imaging.

用于纤维环靶向椎间盘退变成像的功能探针。

• DOI: 10.1117/1.jbo.18.10.101308
• 发表时间: 2013
• 期刊: Journal of biomedical optics
• 影响因子: 3.5
• 作者: Kim,Hye-Yeong;Mcclincy,Michael;Vo,NamV;Sowa,GwendolynA;Kang,JamesD;Bai,Mingfeng
• 通讯作者: Bai,Mingfeng

Effects of secreted factors in culture medium of annulus fibrosus cells on microvascular endothelial cells: elucidating the possible pathomechanisms of matrix degradation and nerve in-growth in disc degeneration.

• DOI: 10.1016/j.joca.2013.12.008
• 发表时间: 2014-02
• 期刊: OSTEOARTHRITIS AND CARTILAGE
• 影响因子: 7
• 作者: Moon, H. J.;Yurube, T.;Lozito, T. P.;Pohl, P.;Hartman, R. A.;Sowa, G. A.;Kang, J. D.;Vo, N. V.
• 通讯作者: Vo, N. V.