Role of Mechanical Forces on Beta-Catenin of Aged Intervertebral Discs

机械力对老化椎间盘β-连环蛋白的作用

• 批准号: 8716377
• 负责人: Nilsson Holguin
• 金额: $ 5.78万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8716377
• 关键词: Age; Aging; Anabolism; Animals; Apoptosis; Back Pain; Biochemical; Biological Markers; Biology; Canis familiaris; Catabolism; Cell Count; Cells; Chondrocytes; Chronic; Data; Development; Disease; Exhibits; Extracellular Matrix Degradation; Failure; Felis catus; Foundations; Gene Targeting; Genes; Genetic; Genetic Models; Genetic Predisposition to Disease; Health; Human; Hydration status; Immobilization; In Situ Nick-End Labeling; Inflammatory; Intervertebral disc structure; Knee joint; Knockout Mice; Lead; Lifting; Ligands; Link; Mechanics; Mediating; Modeling; Molecular; Morphology; Mus; Musculoskeletal; Normal Cell; Outcome; Pathway interactions; Physiological; Play; Proteins; Publishing; Reporter; Reporting; Research; Risk; Rodent; Role; Signal Transduction; Source; Spinal; Staining method; Stains; Structure; Surface; Tail; Techniques; Testing; Therapeutic; Tissues; Transgenic Mice; United States; Weight-Bearing state; Western Blotting; Work; age related; aged; aggrecanase; articular cartilage; beta catenin; bone; clinically relevant; cytokine; experience; extracellular; in vivo; insight; instrument; internal control; intervertebral disk degeneration; novel therapeutics; prevent; response; socioeconomics; spine bone structure; tool; transcription factor; young adult

DESCRIPTION (provided by applicant): Supra-physiological activity, aging and genetic factors may initiate intervertebral disc degeneration, which is characterized by, but not limited to, loss f hydration, altered concentrations of matrix constituents, mechanical stiffening and ultimately back pain. Excessive mechanical loads on tail discs, as analogous to those engendered by strenuous lifting, induce aspects of disc degeneration. However, studies of degeneration using mechanical loading focus on describing the consequences to disc structure and its matrix constituents with little insight into the underlying mechanism(s). Further, the risk of disc degeneration increases with age and therefore, it is important to evaluate the influence of aging on the response to deleterious loading. beta-Catenin is regulated by the canonical Wnt pathway and is putatively involved in the catabolism of intervertebral discs. Extracellular Wnt ligands are upstream regulators of transcription factor beta-catenin, which accumulates in the cells of human degenerated discs, and cells from canines known to have an age-related propensity for degeneration. Suppression of beta-catenin signaling in chondrocytes immersed in inflammatory cytokines mitigates the expression of catabolic markers, suggesting that targeting this pathway may have therapeutic potential. We will combine our experience with murine loading models and genetic tools to determine the role of beta-catenin activation in disc degeneration induced by mechanical loading. The structural-, cellular- and molecular- level consequences of mechanical overloading in a reporter mouse of beta-Catenin activation and a conditional knockout mouse of beta-catenin in young-adult and aged mice. This research will impact the field of intervertebral disc mechano-biology by identifying the involvement of beta-catenin in a model of disc degeneration and help provide a mechanism upon which to develop treatments capable of curbing or preventing disc degeneration.

描述（由申请人提供）：超生理活动、衰老和遗传因素可能引发椎间盘退变，其特征在于但不限于水合作用丧失、基质成分浓度改变、机械性硬化和最终背痛。尾盘上的过度机械负荷，类似于剧烈提升所产生的负荷，会引起椎间盘退变。然而，使用机械负荷进行的退变研究侧重于描述对椎间盘结构及其基质成分的影响，而对潜在机制的了解很少。此外，椎间盘退变的风险随着年龄的增长而增加，因此，重要的是要评估老化对有害负荷反应的影响。β-连环蛋白受经典Wnt通路调节，并且可能参与椎间盘的catenin。细胞外Wnt配体是 转录因子β-连环蛋白的上游调节因子，其在人类退化椎间盘的细胞中积累，以及来自已知具有与年龄相关的退化倾向的犬的细胞。抑制沉浸在炎性细胞因子中的软骨细胞中的β-连环蛋白信号传导减轻了分解代谢标志物的表达，这表明靶向该途径可能具有治疗潜力。我们将联合收割机结合我们的经验与小鼠负荷模型和遗传工具，以确定β-连环蛋白激活在机械负荷诱导的椎间盘退变中的作用。在β-连环蛋白激活的报告小鼠和β-连环蛋白的条件性敲除小鼠中，在成年和老年小鼠中机械过载的结构、细胞和分子水平后果。这项研究将通过确定β-连环蛋白参与椎间盘退变模型来影响椎间盘机械生物学领域，并帮助提供一种机制，以开发能够抑制或预防椎间盘退变的治疗方法。