PTH Attenuation of Spinal Degeneration During Aging PI Janet Crane

PTH 对衰老过程中脊柱退化的衰减 PI Janet Crane

• 批准号: 10556418
• 负责人: Janet Crane
• 金额: $ 27.25万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10556418
• 关键词: Acceleration; Address; Affect; Aging; Analgesics; Attenuated; Axon; Biology; Body Weight; Bone Marrow; Bone remodeling; Calcium; Cartilage; Cell Size; Cells; Chondrocytes; Cilia; Clinical; Clinical Trials Design; Complex; Data; Deceleration; Development; Diffusion; Disease; Elderly; Etiology; Functional disorder; Genetic; Histopathologic Grade; Homeostasis; Hormones; Human; Hypersensitivity; Hypertrophy; Impairment; In Vitro; Inflammatory; Injections; Intervertebral disc structure; Joints; Knock-out; Knockout Mice; Low Back Pain; Magnetic Resonance Imaging; Mechanical Stress; Mechanics; Mediating; Microfluidics; Modeling; Mus; Muscle; Neurons; Neurosciences; Nociception; Nociceptors; Nutrient; Operative Surgical Procedures; Osteoblasts; Osteogenesis; PTH gene; Pain; Parathyroid Hormone Receptor; Pathologic; Patients; Permeability; Persons; Pharmaceutical Preparations; Phenotype; Physical activity; Physicians; Physiologic Ossification; Play; Population; Porosity; Process; Property; Quality of life; Rejuvenation; Replacement Arthroplasty; Reporter; Reporting; Risk; Role; Scientist; Sclerosis; Sensory; Signal Pathway; Signal Transduction; Skeleton; Spinal; Spinal Fusion; Spinal Ganglia; Structural defect; Structure; System; Thick; Thinness; Translations; Vacuole; Validation; Vertebral column; aged; attenuation; bone; cartilaginous; cellular targeting; disability; drug development; frailty; hormonal signals; human disease; human model; improved; intervertebral disk degeneration; joint destruction; mechanical allodynia; mechanical load; mechanical properties; mechanotransduction; mineralization; mouse model; nerve supply; nucleus pulposus; pain behavior; pain relief; remediation; soft tissue; solute; spine bone structure; symptom treatment; symptomatology; transmission process; vertebra body

SUMMARY Low back pain is the leading cause of disability, driven predominantly by aging. Pain contributes to frailty by lowering quality of life and limiting physical activities. Intervertebral disc (IVD) degeneration is the most common cause of low back pain, but is a non-specific finding. No cause-directed, mechanism-based medications protect the spine from progression of degeneration and pain. The spine is a complex joint, built from alternating bony vertebrae and IVD. The vertebral endplate forms a structural boundary between the IVD and the vertebral body. Recent studies have implicated that the vertebral endplate plays a key role in the development of spinal degeneration and low back pain. We have recently reported that daily administration of parathyroid hormone (PTH) in aged mice for two months increases IVD cell size, restoring the vacuoles and rejuvenating the IVD. We have also found that cartilaginous endplates become ossified and porous during aging, which induces sensory innervation for spinal hypersensitivity. Our preliminary data demonstrates that endplate sclerosis improves with PTH administration. Most importantly, we have found that the aberrant innervation of the endplate is reversed with PTH and is associated with a reduction in pain behaviors in the IVD mouse models. We hypothesize that PTH stimulated anabolic bone formation remodels the sclerotic, porous EP to reduce aberrant nociceptive innervation. In this project, we will pursue the following specific aims: Aim 1: Examine vertebral endplate remodeling in the process of PTH-induced rejuvenation of IVD; Aim 2: Identify cellular target of PTH-induced remodeling of porous vertebral endplates; and Aim 3: Determine the mechanism of PTH-induced reduction of sensory innervation and improved pain behaviors. Our study team is comprised of basic scientists with expertise in bone biology regarding PTH cell signaling mechanisms and neuroscience regarding nociceptor neuronal activity, as well as, physician-scientists with translation expertise in mouse models of human disease, spinal degeneration, and clinical use of PTH. We are uniquely suited to further understand the mechanistic actions of PTH and potential as a disease modifying treatment of low back pain. Understanding the mechanism of PTH treatment of low back pain will provide necessary data to inform further drug development and clinical trial designs exploring activation of the PTH signaling pathway as a disease-modifying treatment of spinal degeneration. .

总结 下背痛是残疾的主要原因，主要是由衰老引起的。疼痛导致虚弱， 降低生活质量和限制身体活动。椎间盘（IVD）退变是最常见的 下背痛的原因，但这是一个非特异性的发现。没有针对病因的，基于机制的药物保护 脊柱的退化和疼痛的进展。脊柱是一个复杂的关节，由交替的骨 椎骨和IVD椎骨终板形成IVD和椎体之间的结构边界。 最近的研究表明，椎体终板在脊柱的发育中起着关键作用， 退化和腰痛。我们最近报道，每天服用甲状旁腺激素 (PTH)在老年小鼠中持续两个月增加IVD细胞大小，恢复空泡并使IVD恢复活力。我们 还发现软骨终板在老化过程中变得骨化和多孔，这诱导感觉神经系统的功能。 脊髓超敏性的神经支配。我们的初步数据表明，终板硬化改善， 甲状旁腺素给药。最重要的是，我们发现终板的异常神经支配被逆转 在IVD小鼠模型中，与PTH相关，并且与疼痛行为的减少相关。我们假设 PTH刺激的合成代谢骨形成重塑了表皮，多孔EP以减少异常伤害性感受 神经支配在这个项目中，我们将追求以下具体目标：目标1：检查椎体终板 目的2：确定PTH诱导的IVD年轻化过程中的细胞靶点; 目的3：确定PTH诱导的椎体终板重建的机制。 感觉神经支配和改善疼痛行为。我们的研究团队由具有专业知识的基础科学家组成 在骨生物学中关于PTH细胞信号传导机制和神经科学中关于伤害感受器神经元 活动，以及在人类疾病小鼠模型，脊柱， 变性和PTH的临床应用。我们是唯一适合进一步了解的机械行动， 甲状旁腺素和潜在的作为一种疾病修改治疗腰痛。了解PTH的机制 治疗腰痛将为进一步的药物开发和临床试验提供必要的数据 设计探索PTH信号通路的激活作为脊髓损伤的疾病改善治疗， 退化 .