Osteoarthritis Progression And Sensory Pathway Alterations

骨关节炎进展和感觉通路改变

• 批准号: 9757504
• 负责人: RICHARD J MILLER
• 金额: $ 66.84万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9757504
• 关键词: Affect; Afferent Neurons; Age; Analgesics; Anatomy; Behavior; C Fiber; Cartilage; Chronic; Chronic Disease; Clinical; Degenerative polyarthritis; Development; Disease; Disease Progression; Esthesia; Evolution; Failure; Fatty acid glycerol esters; Female; Fiber; Future; G-Protein-Coupled Receptors; Gated Ion Channel; Generations; Genetic; Health; Hindlimb; Image; Inflammation; Ion Channel Gating; Joints; Knee; Knee joint; Label; Ligaments; Ligands; Maintenance; Mechanics; Mechanoreceptors; Medial meniscus structure; Mediating; Medical; Meniscus structure of joint; Methods; Microscopy; Modeling; Monitor; Mus; Muscle; NGFR Protein; Nature; Nerve; Neuraxis; Neurobiology; Neuronal Plasticity; Neurons; Nociception; Nociceptors; Operative Surgical Procedures; Organ; Pain; Parvalbumins; Pathology; Pathway interactions; Patients; Pattern; Peripheral; Reporter; Rest; Sensory; Spinal Ganglia; Stimulus; Synovial Membrane; TRPV1 gene; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Tissues; Translating; Weight-Bearing state; base; behavior change; biophysical techniques; central sensitization; designer receptors exclusively activated by designer drugs; dorsal horn; experience; in vivo; joint injury; joint mobilization; male; nerve supply; novel; novel strategies; novel therapeutics; osteoarthritis pain; pain behavior; pressure; receptor; response; subchondral bone; targeted treatment; therapeutic development

Project Summary There is an urgent need for new therapeutic agents that treat the pain associated with osteoarthritis (OA). OA is a chronic disease, and as disease progresses, patients can describe different types of pain, including pain on weightbearing or joint movement, and pain at rest. Some patients display signs of peripheral and/or central sensitization. Compelling clinical evidence suggests that ongoing peripheral input from the OA joint drives pain and sensitization. We have developed the murine DMM (destabilization of the medial meniscus) model to study the chronic nature of the disease and the different pain behaviors associated with progressive joint damage. The overarching aim is to characterize anatomical and functional alterations in the sensory innervation of the joint. We have uncovered that in the course of experimental OA, NaV1.8 nociceptors undergo profound, and previously unappreciated, plasticity at all levels (in the knee joint, in the DRG, and in the dorsal horn) in a precisely evolving manner. Recently, it has become clear that sensory neurons can be classified based on unique patterns of expression of molecules that underlie different aspects of somatic sensation. Specifically, NaV1.8 neurons comprise distinct functional subsets, including heat-sensitive TRPV1 neurons, mechanosensitive Mrgprd C-fibers, TH+ C-low threshold mechanoreceptors (C-LTMR), and silent CHRNA3 fibers. Another subset of potential relevance to OA pain is TrkA+, expressing the receptor for Nerve Growth Factor. We hypothesize that specific temporospatial changes in these subpopulations mediate the evolution of pain behaviors during OA progression. Our experimental plan considers two complementary aims to study (1) temporal and spatial contributions (which nerves are present and functional in the OA joint, where and when?); and (2) how we may target these specific neuronal subsets to examine effects on pain behaviors and joint health. Specific Aim 1 aims to define temporal and spatial neuroplasticity of knee innervation in the context of OA joint pathology and pain. We have used a variety of Cre/Flp drivers to produce lines of fluorescent reporter mice specific for distinct subsets of nociceptive, mechanosensitive, and proprioceptive (parvalbumin, PV) DRG neurons. We will use these mice to define anatomical and functional changes in knee innervation, using confocal and lightsheet microscopy, in vivo Ca2+ imaging, and transient chemogenetic silencing of specific neuronal subsets. Specific Aim 2 aims to target specific neuronal subsets and examine the effect on OA disease (pain and joint damage), in order to explore how our findings may translate to new approaches for OA pain. We will determine the effects of chronic chemogenetic silencing of neuronal subpopulations on OA pain and joint damage. We will also study the “receptome” specific to DRG subpopulations in order to develop targeted therapeutic interventions. We propose that the identification of neuronal subpopulations that mediate OA pain behaviors will allow them to be specifically targeted at specific stages of the disease and this will result in novel, more efficacious and safer therapeutic approaches to OA pain.

项目摘要 迫切需要治疗与骨关节炎（OA）相关的疼痛的新治疗剂。OA 是一种慢性疾病，随着疾病的进展，患者可以描述不同类型的疼痛，包括疼痛 在负重或关节运动，和休息时疼痛。一些患者显示外周和/或中枢神经系统的体征， 致敏令人信服的临床证据表明，来自OA关节的持续外周输入驱动疼痛 和敏化作用。我们已经开发了小鼠DMM（内侧半月板不稳定）模型来研究 疾病的慢性性质和与进行性关节损伤相关的不同疼痛行为。 总体目标是表征感觉神经支配的解剖学和功能变化， 关节我们已经发现，在实验性OA的过程中，NaV1.8伤害感受器经历了深刻的， 以前未被认识到的是，在所有水平（膝关节，背根神经节和背角）的可塑性， 精确进化的方式。最近，已经清楚的是，感觉神经元可以根据 这些独特的分子表达模式构成了躯体感觉的不同方面。具体地说， NaV1.8神经元包括不同的功能亚群，包括热敏TRPV 1神经元， 机械敏感性Mrgprd C-纤维、TH+ C-低阈值机械感受器（C-LTMR）和沉默CHRNA 3 纤维与OA疼痛潜在相关的另一个子集是TrkA+，表达神经生长受体 因子我们假设这些亚群中特定的时空变化介导了 OA进展期间的疼痛行为。我们的实验计划考虑了两个互补的研究目标（1） 时间和空间贡献（OA关节中存在哪些神经并发挥功能，何时何地？）; 以及（2）我们如何靶向这些特定的神经元亚群来检查对疼痛行为和关节的影响 健康具体目标1旨在定义膝关节神经支配的时间和空间神经可塑性， OA关节病理和疼痛。我们已经使用了多种Cre/Flp驱动程序来产生荧光报告基因的线 对伤害感受性、机械敏感性和本体感受性（小白蛋白，PV）DRG的不同亚群特异的小鼠 神经元我们将使用这些小鼠来定义膝关节神经支配的解剖学和功能变化， 共聚焦和光片显微镜，体内Ca 2+成像，和特异性的瞬时化学遗传沉默， 神经元亚群特定目标2旨在靶向特定神经元亚群并检查对OA的影响 疾病（疼痛和关节损伤），以探索我们的研究结果如何转化为OA的新方法 痛苦我们将确定神经元亚群的慢性化学基因沉默对OA疼痛的影响 和关节损伤我们还将研究DRG亚群特异性的“受体组”，以开发 有针对性的治疗干预。我们建议，鉴定神经元亚群，介导 OA疼痛行为将允许他们在疾病的特定阶段被专门针对，这将 导致新的，更有效和更安全的治疗OA疼痛的方法。