Osteoarthritis Progression And Sensory Pathway Alterations

骨关节炎进展和感觉通路改变

• 批准号: 10169854
• 负责人: RICHARD J MILLER
• 金额: $ 16.28万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10169854
• 关键词: Afferent Neurons; Analgesics; Anatomy; C Fiber; Chronic; Chronic Disease; Clinical; Degenerative polyarthritis; Development; Disease; Esthesia; Evolution; Fiber; Generations; Health; Image; Joints; Knee; Knee joint; Maintenance; Mechanoreceptors; Medial meniscus structure; Mediating; Medical; Microscopy; Modeling; Mus; NGFR Protein; Nature; Nerve; Neurobiology; Neuronal Plasticity; Neurons; Nociception; Nociceptors; Pain; Parvalbumins; Pathology; Pathway interactions; Patients; Pattern; Peripheral; Reporter; Rest; Sensory; TRPV1 gene; Techniques; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Translating; Weight-Bearing state; base; central sensitization; dorsal horn; in vivo; joint injury; joint mobilization; nerve supply; novel; novel strategies; novel therapeutics; osteoarthritis pain; pain behavior; targeted treatment

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.

项目概要 迫切需要治疗骨关节炎 (OA) 相关疼痛的新治疗药物。 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 负重或关节运动，以及休息时疼痛，一些患者表现出外周和/或中枢的症状。 令人信服的临床证据表明，骨关节炎关节的持续外周输入会导致疼痛。 我们开发了小鼠 DMM（内侧半月板不稳定）模型来研究。 该疾病的慢性性质以及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改变 我们发现，在实验性 OA 过程中，NaV1.8 伤害感受器经历了深刻的、并且 以前未被认识到，各个层面（膝关节、DRG 和背角）的可塑性 最近，人们已经清楚，感觉神经元可以根据其精确的进化方式进行分类。 构成躯体感觉不同方面的独特分子表达模式。 NaV1.8 神经元包含不同的功能子集，包括热敏感 TRPV1 神经元、 机械敏感 Mrgprd C 纤维、TH+ C 低阈值机械感受器 (C-LTMR) 和沉默 CHRNA3 与 OA 疼痛潜在相关的另一个纤维是 TrkA+，表达神经生长受体。 我们认为这些亚群的特定时空变化介导了进化。 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作用，何时何地？）； （2）我们如何针对这些特定的神经子集来检查对疼痛行为和关节的影响 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 关节病理学和疼痛 我们使用了多种 Cre/Flp 驱动程序来生产荧光报告基因线。 对伤害感受、机械敏感和本体感受（小白蛋白，PV）DRG 的不同子集具有特异性的小鼠 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，使用 共聚焦和光片显微镜、体内 Ca2+ 成像以及特定的瞬时化学遗传学沉默 具体目标 2 旨在针对特定神经子集并检查对 OA 的影响。 疾病（疼痛和关节损伤），以探索我们的发现如何转化为 OA 的新方法 我们将确定神经元亚群的慢性化学遗传学沉默对骨关节炎疼痛的影响。 我们还将研究 DRG 亚群特有的“受体组”，以便开发。 我们建议鉴定介导的神经亚群。 OA 疼痛行为将使他们能够专门针对疾病的特定阶段，这将 从而产生新颖、更有效、更安全的骨关节炎疼痛治疗方法。