Mechanisms of Cellular Senescence Driving Intervertebral Disc Aging through Local Cell Autonomous and Systemic Non-Cell Autonomous Processes

细胞衰老通过局部细胞自主和全身非细胞自主过程驱动椎间盘老化的机制

• 批准号: 10635092
• 负责人: NAM V VO
• 金额: $ 52.69万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10635092
• 关键词: Acceleration; Age Months; Aging; Automobile Driving; Back Pain; Behavior; Biology; Blood; CDKN1A gene; CDKN2A gene; Cell Aging; Cell Culture Techniques; Cell Cycle Proteins; Cell Therapy; Cells; Chronic; Clinical; DNA Damage; DNA Repair Endonuclease; DNA Repair Gene; Dasatinib; Data; Disease; ERCC1 gene; Economic Burden; Economics; Endocrine; Event; Exposure to; Funding; Genetic; Human; Immune system; Immunological Models; Inflammatory; Intervention; Intervertebral disc structure; Knock-out; Knowledge; LOX gene; Laboratories; Low Back Pain; Maps; Mediating; Modeling; Molecular; Mouse Strains; Mus; Mutagens; Parabiosis; Pathway interactions; Pharmaceutical Preparations; Phenotype; Process; Public Health; Quercetin; Regenerative research; Reporter; Research; Risk Factors; Role; Signal Transduction; Spinal Diseases; Syndrome; Testing; Therapeutic; Therapeutic Effect; Tissues; Transgenic Mice; Transgenic Organisms; Vertebral column; age related; aged; cell type; chronic back pain; disability; disc regeneration; experimental study; fisetin; health economics; human model; innovation; intervertebral disk degeneration; mouse model; novel; promoter; senescence; socioeconomics; success

Project summary Intervertebral disc degeneration (IDD) underlies many spinal disorders resulting in debilitating back pain, disability, and tremendous economic loss. Aging is the greatest risk factor for IDD and yet the biology of disc aging is still poorly understood. Our prior research demonstrated that persistent DNA damage promotes senescent cells resulting in their acquisition of the senescence-associated secretory phenotype (SASP) that produces copious inflammatory and catabolic factors that promote disc matrix loss, a universal feature of disc aging and degeneration. While these findings greatly advance our understanding of disc aging, they also raise important questions. Does cellular senescence mainly drive disc aging locally, systemically, or both? In other words, do senescent disc cells with tissue-destroying SASP locally drive disc aging in a cell-autonomous manner, or do senescent cells from other tissues systemically promote disc aging through the endocrine action of their SASP and signaling factors through non-cell autonomous mechanisms? Moreover, which of the two major cellular senescence pathways, p16INK4a or p21Cip1, predominantly drive the local cell-autonomous effects and the systemic non-cell autonomous effects on disc aging? Based on our preliminary data, we hypothesize that local effects of p21-mediated disc cellular senescence are only partially responsible for driving age dependent IDD, and that contribution from p16-mediated systemic cellular senescence is necessary to fully account for the observed disc aging phenotype. We propose three specific aims to test this hypothesis using several innovative transgenic mouse strains: (1) Determine the relative contributions of local (cell autonomous) and systemic (non-cell autonomous) processes in driving disc cellular senescence and age- dependent IDD; (2) Determine the relative contributions of p21CIP1 and p16INK4a -mediated cellular senescence on age-dependent IDD; and (3) Test whether senolytic treatment can slow age-dependent IDD. Completion of the proposed studies will determine whether disc aging is driven predominantly by local or systemic processes and whether these processes are mediated primarily through the p21Cip1 or p16INK4a cellular senescence pathway. Finally, our proposed studies will identify novel senolytic drugs for treating and slowing age- dependent IDD.

项目摘要 椎间盘退变（IDD）是许多脊柱疾病的基础，导致背部衰弱 痛苦残疾和巨大的经济损失衰老是碘缺乏病的最大危险因素， 椎间盘老化仍然知之甚少。我们之前的研究表明，持续的DNA损伤会促进 衰老细胞导致其获得衰老相关分泌表型（SASP）， 产生大量的炎症和分解代谢因子，促进椎间盘基质丢失，这是椎间盘的普遍特征， 老化和退化。虽然这些发现极大地推进了我们对椎间盘老化的理解， 重要的问题细胞衰老主要是局部、全身还是两者共同驱动椎间盘老化？换句 换句话说，具有组织破坏性SASP的衰老椎间盘细胞是否在细胞自主的 或者来自其他组织的衰老细胞通过内分泌作用系统性地促进椎间盘衰老 通过非细胞自主机制表达SASP和信号因子？此外，这两个 主要的细胞衰老途径，p16 INK 4a或p21 Cip 1，主要驱动局部细胞自主效应 以及系统性非细胞自主作用对椎间盘老化的影响？根据我们的初步数据，我们假设 p21介导的椎间盘细胞衰老的局部效应仅部分导致年龄增长， 依赖性IDD，p16介导的系统性细胞衰老的贡献是必要的， 完全解释了观察到的椎间盘老化表型。我们提出了三个具体目标来测试这一点 假设使用几种创新的转基因小鼠品系：（1）确定局部的相对贡献 (cell自主）和系统（非细胞自主）过程驱动椎间盘细胞衰老和衰老- （2）确定p21 CIP 1和p16 INK 4a介导的细胞衰老的相对贡献 （3）检测抗衰老治疗是否能延缓年龄依赖性IDD。完成 拟议的研究将确定椎间盘老化主要是由局部还是系统性过程驱动的 以及这些过程是否主要通过p21 Cip 1或p16 INK 4a细胞衰老介导 通路最后，我们提出的研究将确定用于治疗和减缓衰老的新型衰老药物- 依赖IDD。