The role of cellular senescence in intervertebral disc aging

细胞衰老在椎间盘老化中的作用

• 批准号: 8478298
• 负责人: NAM V VO
• 金额: $ 29.96万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8478298
• 关键词: AP20187; Age; Aging; Alleles; Attenuated; Automobile Driving; Back Pain; CDKN2A gene; Catabolism; Cell Aging; Cells; Characteristics; Chimeric Proteins; DNA Damage; DNA Repair; Data; Defect; Development; Dimerization; Disease; Due Process; Economics; Equilibrium; Exhibits; Extracellular Matrix; Fibroblasts; Gene Expression Profiling; Genetic; Genotoxic Stress; Goals; Homeostasis; Human; In Situ; Incidence; Inflammatory; Interleukin-6; Intervertebral disc structure; Link; MMP3 gene; Matrix Metalloproteinases; Measures; Mediating; Mediator of activation protein; Metabolic; Mouse Strains; Mus; NF-kappa B; Operative Surgical Procedures; Organ; Organism; Pathway interactions; Peptide Hydrolases; Pharmaceutical Preparations; Phenotype; Population; Positioning Attribute; Process; Progeria; Proteins; Proteoglycan; Quality of life; Reporting; Research; Research Personnel; Risk Factors; Role; Seminal; Severities; Specimen; Spinal; Stimulus; Stress; Structural Protein; Structure; Surgeon; Tacrolimus Binding Proteins; Testing; Therapeutic Intervention; Tissues; Vertebral column; Weight-Bearing state; Work; age group; age related; aged; aggrecan; aggrecanase; aging population; aspergillopepsin II; base; caspase-8; cell type; cellular targeting; chronic back pain; cytokine; disability; in vivo; intervertebral disk degeneration; medical specialties; mouse model; novel; p65; paracrine; premature; prevent; promoter; public health relevance; research study; response; senescence; socioeconomics; theories

DESCRIPTION (provided by applicant): Intervertebral disc degeneration (IDD) underlies many spinal disorders resulting in debilitating back pain, disability, and tremendous economic loss. Several etiologic factors of IDD have been identified, including aging. Loss of disc matrix proteoglycans (PG), an important class of structural protein for counteracting load, is a universal feature of IDD. With aging, there is progressive loss of disc matrix proteoglycans, but the precise mechanisms by which aging promotes disc PG loss IDD are poorly understood. This represents the next major gap in disc aging research. Disc PG loss is primary driven by cells with perturbed PG homeostasis, whereby PG synthesis is down regulated while PG catabolism is up regulated. Senescent cells accumulate in various tissues and have been thought to promote aging. Elevated senescent cells have also been detected in aged discs, but it is not known if these cells exhibit perturbed PG homeostasis that causes net PG loss during aging. Recent studies demonstrated that stress-induced senescent fibroblasts secrete numerous inflammatory cytokines and matrix proteinases, a feature termed senescence associated secretory phenotype (SASP), which can have profound paracrine catabolic effects on neighboring cells and extracellular matrix. We recently discovered from studies using the DNA repair-deficient mouse model of accelerated aging (Ercc1-/? mice) that DNA damage is a key driver of age-related disc PG loss and that NF-?B pathway is important in this process. Because DNA damage and NF-?B activity are important for the formation of cellular senescence, we hypothesized that NF-?B mediates DNA damage-induced cellular senescence, which perturbs disc PG homeostasis, leading to PG loss and age-related IDD. To test our hypothesis, we proposed to determine in Aim #1: the role of NF-?B in mediating the establishment of cellular senescence in discs of mice genetically depleted of the p65 subunit of NF-?B, Aim #2: the metabolic phenotype of senescent disc cells as it relates to PG homeostasis and SASP, and Aim #3: the causal role of cellular senescence in driving disc aging using genetic mouse models manipulated to reduce the level of cellular senescence. Successful completion of the proposed experiments will determine whether cellular senescence promotes disc aging and provide a specific target for therapeutic interventions for delaying the onset or ameliorating the severity of age-related IDD, the incidence of which is expected to rise rapidly with the fast growing aging population. I will be leading the collaborative team effort to tackle this proposed research. Our well- integrated team consists of Laura Niedernhofer, a mouse geneticist and a leader in DNA repair/aging research, Paul Robbins, the NF-?B expert, Peter Roughley, the aggrecan biochemist, Gwendolyn Sowa, a mechanobiologist with a specialty in disc gene expression profiling, and James Kang, spine surgeon and disc researcher who will provide human surgical disc specimen for analysis.

描述（由申请人提供）：椎间盘退变（IDD）是许多脊柱疾病的基础，导致衰弱性背痛、残疾和巨大的经济损失。 IDD的几个病因因素已经确定，包括衰老。椎间盘基质蛋白聚糖（PG）是一类重要的结构蛋白，用于抵消负荷，其丢失是一种普遍的 IDD的特点。 随着年龄的增长，椎间盘基质蛋白多糖逐渐丢失，但对年龄促进椎间盘PG丢失IDD的确切机制知之甚少。这代表了椎间盘老化研究的下一个主要空白。椎间盘PG丢失主要由PG稳态受到干扰的细胞驱动，由此PG合成下调，而PG催化剂上调。 衰老细胞在各种组织中积累，并被认为会促进衰老。 在老年椎间盘中也检测到了升高的衰老细胞，但尚不清楚这些细胞是否表现出在衰老过程中导致净PG损失的PG稳态紊乱。近年来的研究表明，应激诱导的衰老成纤维细胞分泌大量的炎性细胞因子和基质蛋白酶，这一特征被称为衰老相关分泌表型（SASP），其可对邻近细胞和细胞外基质产生深刻的旁分泌分解代谢作用。 我们最近从使用DNA修复缺陷小鼠加速老化模型（Ercc 1-/？小鼠），DNA损伤是一个关键的驱动程序与年龄相关的光盘PG损失和NF-？B途径在此过程中起重要作用。因为DNA损伤和NF-？B活性对细胞衰老的形成是重要的，我们推测NF-？B介导DNA损伤诱导的细胞衰老，从而扰乱椎间盘PG稳态，导致PG丢失和年龄相关的IDD。为了验证我们的假设，我们提出了确定目标#1：NF-？B在介导NF-κ B p65亚基基因缺失小鼠椎间盘细胞衰老中的作用？B，目标2：衰老椎间盘细胞的代谢表型，因为它与PG内稳态和SASP有关，以及目标#3：细胞衰老在驱动椎间盘衰老中的因果作用，使用经操作以降低细胞衰老水平的遗传小鼠模型。成功完成拟议的实验将确定细胞衰老是否促进椎间盘衰老，并为治疗干预提供一个特定的目标，以延迟年龄相关的IDD的发病或改善其严重程度，预计随着人口老龄化的快速增长，IDD的发病率将迅速上升。我将领导合作团队努力解决这项拟议的研究。我们整合良好的团队由Laura Niedernhofer，小鼠遗传学家和DNA修复/衰老研究的领导者，Paul Robbins，NF-？B专家，聚集蛋白聚糖生物化学家Peter Roughley，椎间盘基因表达谱专业机械生物学家Gwendolyn Sowa，以及脊柱外科医生和椎间盘研究员James Kang，他将提供人类手术椎间盘标本进行分析。