Interaction of sex effects and intervertebral disc degeneration in a rat model of chronic back pain pathogenesis

慢性背痛发病机制大鼠模型中性别效应与椎间盘退变的相互作用

基本信息

批准号：
9978711
负责人：
Grace Ellen Mosley
金额：
$ 5.05万
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：
2018
资助国家：
美国
起止时间：
2018-09-04 至 2021-09-03
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9978711
关键词：
Abdomen Acute Address Affect Anterior Anterolateral Area Back Pain Behavioral Bilateral Biological Biological Assay Biomechanics Chest Chronic Chronic low back pain Clinical Medicine Complementary Health Complex Control Animal Development Disease Doctor of Philosophy Dorsal Epidemic Fellowship Female Fluoro-Gold Functional disorder Funding Ganglia Gene Expression Gene Expression Profile Genes Genetic Transcription Goals Grant Height Histologic Human Hyperalgesia Immune system Impairment Injections Injury Integrative Medicine Intervention Intervertebral disc structure Investigation Knowledge Label Lead Location Low Back Pain Lumbar Regions Measurement Measures Mechanics Medicine Modality Modeling Molecular Morphology Motion Needles Nervous system structure Neurons Neurosciences Operative Surgical Procedures Opioid Analgesics Orthopedics Outcome Pain Pathogenesis Pathologic Pathology Pathway interactions Pattern Plant Roots Play Population Pre-Clinical Model Property Protocols documentation Puncture procedure RNA Radial Rattus Refractory Research Risk Rodent Model Roentgen Rays Role Science Scientist Screening procedure Sensory Sex Differences Spinal Spinal Ganglia Spinal cord posterior horn Sprague-Dawley Rats Structure Surgical incisions TNF gene Testing Therapeutic Intervention Time Torsion Tracer Training Vertebral column Woman behavior test chronic back pain chronic pain chronic pain management chronic painful condition clinically significant cohort design disability discogenic pain healing improved in vivo innovation intervertebral disk degeneration male mechanical allodynia men nerve supply new therapeutic target non-opioid analgesic novel opioid epidemic opioid use pain patient pain sensitivity receptor response sex socioeconomics spinal disk injury targeted treatment therapeutic target transcriptome sequencing

项目摘要

Intervertebral disc (IVD) degeneration is a debilitating disorder implicated in the pathogenesis of chronic low back pain, a leading cause of global disability and a contributor to the opioid crisis in the USA. However, the interaction between IVD degeneration and the nervous system that leads to chronic low back pain is not well understood. Further, while both spine impairments and chronic pain conditions are more common in women, there are almost no studies examining the possible effects of sex on the relationship between IVD degeneration and nervous system changes in the setting of chronic low back pain. The overall goal of the proposed research is to determine how IVD degeneration, pain across sensory modalities, and nervous system gene expression changes interact in the pathogenesis of chronic low back pain, and how these complicated relationships may differ between males and females. The proposed studies apply a unique rat model to identify novel targets for non-opioid therapies for chronic low back pain, that may enable more precise therapeutic targeting of the pathologic changes in chronic low back pain, without the risks of opioid usage. Aim 1 will determine how sex and IVD injury interact in the induction of structural, morphological, and biomechanical changes in the IVD in degeneration. Aim 2 measures sex differences in pain at the behavioral level by testing for changes in pain sensitivity across multiple sensory modalities. Aim 3 evaluates the transcription-level changes in the nervous system that likely play a significant role in the pain sensitivity measured in Aim 2, in order to identify possible therapeutic targets. This project is significant because of the translational potential to the highly clinically significant problem of discogenic back pain. The approach is innovative because it investigates the influence of sex on the pathogenesis of chronic back pain originating from intervertebral disc injury and degeneration. Improved understanding of the influence of sex on intervertebral structure, morphology, and biomechanics, and via what molecular pathways they may induce a chronic pain state in the nervous system may enable better-targeted therapies to replace the use of opioid analgesics for chronic low back pain. Such knowledge would be highly significant to the fields of orthopaedics, neuroscience, and medicine, as clarifying these interactions may improve current treatments and reduce the global suffering from chronic back pain. This fellowship application will also fund MD/PhD studies of a highly promising clinician- scientist with commitment to the application of complementary and integrative health strategies to manage chronic low back pain.

椎间盘（IVD）变性是一种使人衰弱的疾病，与慢性低的发病机理有关背痛是全球残疾的主要原因，也是美国阿片类药物危机的贡献者。但是， IVD变性与导致慢性下背痛的神经系统之间的相互作用不好理解。此外，尽管脊柱障碍和慢性疼痛状况在女性中更为普遍，但几乎没有研究检查性别对IVD之间关系的可能影响慢性下背痛的环境中的退化和神经系统变化。总体目标拟议的研究是确定IVD变性，跨感觉方式的疼痛和神经系统如何基因表达的变化在慢性下腰痛的发病机理中相互作用，以及这些如何复杂男性和女性之间的关系可能有所不同。拟议的研究采用独特的大鼠模型来识别慢性下腰痛的非阿片类药物疗法的新靶标，这可能使得更精确的治疗靶向慢性腰痛的病理变化，而没有阿片类药物使用的风险。目标1意志确定性别和IVD损伤如何在诱导结构，形态和生物力学的诱导中相互作用 IVD变性的变化。 AIM 2通过测试在行为层面疼痛的性别差异对于多种感觉方式的疼痛敏感性的变化。 AIM 3评估转录级神经系统的变化可能在AIM 2中测得的疼痛敏感性中起重要作用为了识别可能的治疗靶标。该项目很重要，因为转化的潜力高度临床意义的腹痛问题。这种方法是创新的，因为它研究性别对椎间盘源自慢性背痛的发病机理的影响伤害和变性。改善了对性别对椎体结构的影响的理解，形态学和生物力学，通过哪种分子途径，它们可能诱导慢性疼痛状态神经系统可以使靶向更好的疗法替代阿片类镇痛药的使用慢性低背痛。这种知识对于骨科，神经科学和医学澄清这些相互作用可能会改善当前治疗，并减少全球苦难慢性背痛。该奖学金申请还将资助高度有希望的临床医生的MD/PHD研究。科学家致力于采用互补和综合健康策略来管理慢性下腰痛。