FoxO Transcription Factors in Spine Aging and Disease

脊柱衰老和疾病中的 FoxO 转录因子

• 批准号: 9169399
• 负责人: Oscar Alvarez-Garcia
• 金额: $ 9.63万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9169399
• 关键词: Adult; Affect; Age; Aging; Antioxidants; Autophagocytosis; Bone Tissue; Boxing; Cartilage; Cell Differentiation process; Characteristics; Chondrocytes; Degenerative polyarthritis; Disease; Disease Progression; Event; Extracellular Matrix; Family; Foundations; Genes; Goals; Homeostasis; Human; Hypertrophy; Injury; Intervertebral disc structure; Knowledge; Kyphosis deformity of spine; Lead; Link; Longevity; Low Back Pain; Measures; Mediator of activation protein; Molecular; Mus; Musculoskeletal; Musculoskeletal Diseases; Oxidative Stress; Pain; Palliative Care; Pathogenesis; Pattern; Play; Proteins; Reporting; Resistance; Risk Factors; Role; Sampling; Signaling Protein; Tamoxifen; Testing; Therapeutic; Time; Tissues; Vertebral column; age related; aged; aggrecan; articular cartilage; cellular longevity; disability; effective therapy; in vivo; innovation; intervertebral disk degeneration; mouse model; new therapeutic target; next generation sequencing; novel; postnatal; potential biomarker; prevent; research study; soft tissue; symptom management; therapeutic target; transcription factor; transcriptomics

ABSTRACT Low back pain is the most common musculoskeletal disease and a major cause of disability. This costly condition affects bone and soft tissues of the spine and the principal underlying cause is degeneration of the intervertebral disc (IVD). Aging is a main risk factor for IVD degeneration (IDD). Age-related changes in the IVD cells and extracellular matrix are thought to compromise tissue homeostasis and trigger the onset of IDD. However, the precise molecular mechanisms underlying IDD are not well understood. The Forkhead box O (FoxO) transcription factors are evolutionarily conserved genes implicated in longevity and cellular homeostasis. Dysregulated FoxO expression and activity has been linked to several age-related diseases.. We have reported that FoxO proteins support resistance to oxidative stress and promote autophagy in human articular chondrocytes, and that FoxO expression is reduced in articular cartilage during aging and osteoarthritis. Our preliminary studies show that FoxO expression is reduced in IVD and endplates of aged mice and that in mice with col2a1cre-driven deletion of FoxO manifest abnormal organization and hypertrophy of the IVD and the cartilaginous endplates. These observations support hypothesis is that FoxO are important factors controlling IVD homeostasis and that a reduction of FoxO expression in IVD is an early event that eventually leads to IVD degeneration. In Aim 1 we will measure the expression of FoxO in human and mouse IVD throughout a broad aging spectrum and different degrees of degeneration, and we will correlate changes in FoxO expression with histopathological changes in IVD and with known mediators of IDD. In Aim 2 we will examine the role of FoxO in spine in vivo by analyzing spontaneous histological and molecular changes in the IVD of aggrecan-CreERT2 -FoxOfl/fl mice with postnatal, tissue-specific deletion of FoxO. The proposed project will establish proof of principle that aging-related reduction in FoxO expression is an early and critical event in IDD pathogenesis. This will provide the foundation for therapeutic approaches aimed at modulating FoxO expression and/or activity to prevent age-related and injury-induced IVD degeneration.

摘要 腰痛是最常见的肌肉骨骼疾病，也是致残的主要原因。这 代价高昂的疾病会影响脊柱的骨骼和软组织，其主要潜在原因是 椎间盘退行性变(IVD)。衰老是IVD变性(IDD)的主要危险因素。 IVD细胞和细胞外基质中与年龄相关的变化被认为损害了组织 动态平衡并触发IDD的发病。然而，潜在的确切分子机制 人们对IDD的了解还不够深入。叉头盒O(FoxO)转录因子在进化过程中 与长寿和细胞动态平衡有关的保守基因。FoxO基因异常表达 而且活动与几种与年龄相关的疾病有关。我们已经报道了FoxO蛋白 支持人类关节软骨细胞抵抗氧化应激并促进自噬，以及 在衰老和骨关节炎过程中，FoxO在关节软骨中的表达减少。我们的预赛 研究表明，FoxO在老年小鼠的IVD和终板中的表达减少，而在小鼠 由col2a1cre驱动的FoxO缺失表现为IVD的异常组织和肥大 还有软骨终板。这些观察结果支持这样一种假设，即FOXO很重要 控制IVD动态平衡的因素和IVD中FoxO表达减少是一个早期事件 这最终会导致IVD退化。在目标1中，我们将测量FoxO在人类中的表达 和小鼠IVD在广泛的衰老光谱和不同程度的退化中，我们 将FoxO表达的变化与IVD的组织病理学变化以及已知的 碘缺乏病的调解人。在目标2中，我们将通过分析FoxO在体内脊柱中的作用来研究FoxO的作用 Aggrecan-CreerT2-FoxOf1/fl小鼠IVD的自发组织学和分子变化 出生后，组织特异性的FoxO缺失。拟议的项目将建立原则证明，即 增龄相关的FoxO表达减少是IDD发病机制中的早期和关键事件。这 将为旨在调节FoxO表达和/或 预防年龄相关和损伤引起的IVD变性的活动。