Repurpose bone therapeutics for intervertebral disc degeneration in aged mice

重新利用骨疗法治疗老年小鼠椎间盘退变

基本信息

批准号：
10445485
负责人：
Nilsson Holguin
金额：
$ 52.54万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-22 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10445485
关键词：
Acute Adult Affect Age Aging Agonist Anabolism Antibodies Attenuated Back Back Pain Behavior Behavioral Model Binding Biophysics Bone structure Cell Proliferation Cells Child Collagen Collection Data Dehydration Dose Early treatment Elderly Ensure Estrogen Antagonists Estrogen Receptor alpha Estrogens Etiology Extracellular Matrix FDA approved Female Generations Genetic Genetic Recombination Glycine decarboxylase Height Histology Homeostasis Hydration status Impairment Individual Inflammation Injections Intervertebral disc structure Knowledge LacZ Genes Ligands Low Back Pain Magnetic Resonance Imaging Maintenance Mechanics Mediating Metabolism Modeling Molecular Mus Natural regeneration Occupations Operative Surgical Procedures Osteogenesis Outcome Ovariectomy Pain Palliative Care Pathway interactions Persons Pharmacology Population Positioning Attribute Postmenopause Prevention Property Proteoglycan Raloxifene Recording of previous events Reporter Signal Pathway Signal Transduction Statistical Data Interpretation Strenuous Exercise Structure Substance P Tail Tamoxifen Testing Therapeutic Time Vertebral column WNT Signaling Pathway Water Woman age related aged aging population analog beta catenin bone bone mass chronic pain disability improved inhibitor intervertebral disk degeneration male mechanical force nucleus pulposus overexpression pain behavior palliative prevent prophylactic response second harmonic sex socioeconomics spinal disk injury stem transcription factor transcriptome sequencing young adult

项目摘要

Project Summary Intervertebral disc degeneration is a major etiological factor of low back pain, which is the #1 cause of job disability worldwide that affects 80% of people at least once in their lifetime. Older individuals are prone to intervertebral disc degeneration by a loss of disc height and hydration. Pain can worsen intervertebral disc degeneration by limiting mobility and reducing the mechanical forces necessary for homeostasis. Therefore, there is an unmet need to safely protect older individuals from intervertebral disc degeneration and, here, we intend to repurpose existing bone therapeutics to reduce/prevent intervertebral disc loss and consequently back pain in the aging population. Intervertebral disc degeneration remains a growing problem because (1) the US geriatric population is projected to outnumber children for the first time in history, (2) the early treatment of intervertebral disc degeneration remains palliative and (3) the ballooning socioeconomic burden. We are uniquely positioned to bridge the knowledge gap in the molecular mechanisms of bone therapeutics to stem intervertebral disc degeneration. Aging and mechanical injury of the intervertebral disc by compression both exacerbate breakdown of the extracellular matrix, but compression stimulates inflammation more so than aging. By contrast, we recently found that deletion of the inhibitor of Wnt/β-Catenin signaling sost, a bone formation anabolic mechanism and the genetic analog approach to anti-sclerostin antibody injection, increases the structural properties and hydration of the intervertebral disc. Another bone therapeutic that shows benefits to the intervertebral disc is anti-resorptive raloxifene, a non-uterine-targeting estrogen agonist, that also increases binding of water to collagen. Use of raloxifene in postmenopausal women is associated with relieving back pain and greater intervertebral disc height than non-treated women. Our studies show that raloxifene increases intervertebral disc height in male and female mice, reduces sex- and age-related intervertebral disc degeneration in female mice, improves metrics of pain-related behavior in old mice and stimulates Wnt and estrogen signaling. Here, we hypothesize that currently available therapeutics will stimulate extracellular matrix anabolism and prevent compression-induced intervertebral disc degeneration in young and aged mice. To test this hypothesis, we propose two aims using aged mice and catabolic compression as models of intervertebral disc degeneration. In aim 1, we will determine whether therapeutics known to activate Wnt signaling will prevent IVD degeneration by injurious mechanical compression in young and aged mice. In aim 2, we will determine whether estrogen signaling prevents IVD degeneration via Wnt signaling and whether prevention can be safely improved by combining the signaling pathways in aged mice. This proposal will repurpose current FDA-approved bone prophylactics that target pathways consistently impacted by intervertebral disc degeneration in variable conditions and may be specifically beneficial to intervertebral disc degeneration in the elderly.

项目概要椎间盘退变是腰痛的主要病因，也是导致工作的第一大原因全球 80% 的人一生中至少会患上一次残疾。由于椎间盘高度和水合作用的丧失而导致椎间盘退变，疼痛会使椎间盘恶化。通过限制活动性和减少体内平衡所需的机械力来实现退化。安全保护老年人免受椎间盘退变的需求尚未得到满足，在这里，我们打算重新利用现有的骨疗法，以减少/防止椎间盘丢失，从而恢复椎间盘退变的疼痛仍然是一个日益严重的问题，因为 (1) 美国预计老年人口数量将在历史上首次超过儿童人数，(2) 早期治疗椎间盘退变仍然是姑息治疗；(3) 社会负担不断增加。具有独特的优势，可以弥合骨治疗分子机制的知识差距椎间盘退变和椎间盘受压造成的机械损伤。加剧细胞外基质的分解，但压力比衰老更能刺激炎症。相比之下，我们最近发现，Wnt/β-Catenin 信号传导抑制剂的缺失（骨形成过程）合成代谢机制和抗硬化素抗体注射的遗传模拟方法，增加了另一种对椎间盘的结构特性和水合作用有益的骨治疗方法。雷洛昔芬是一种抗椎间盘吸收的药物，它是一种非子宫靶向雌激素激动剂，它也会增加水与胶原蛋白的结合在绝经后妇女中使用雷洛昔芬与缓解背痛有关。我们的研究表明，雷洛昔芬会增加椎间盘高度。雄性和雌性小鼠的椎间盘高度，减少与性别和年龄相关的椎间盘退变在雌性小鼠中，改善老年小鼠疼痛相关行为的指标并刺激 Wnt 和雌激素信号传导。在这里，我们追求当前可用的治疗方法将刺激细胞外基质合成代谢和防止年轻和老年小鼠受压引起的椎间盘退变为了检验这一假设，我们提出了两个目标，使用老年小鼠和分解代谢压缩作为椎间盘退变的模型。在目标 1 中，我们将确定已知激活 Wnt 信号传导的疗法是否可以预防 IVD 退化在目标 2 中，我们将确定雌激素是否对年轻和老年小鼠造成伤害。信号传导通过 Wnt 信号传导预防 IVD 变性，以及是否可以通过以下方式安全地改善预防效果：结合老年小鼠的信号通路，该提案将重新利用目前 FDA 批准的骨骼。针对不同情况下持续受到椎间盘退变影响的通路的预防剂条件，可能特别有益于老年人的椎间盘退变。