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.

项目摘要 迫切需要对治疗与骨关节炎相关的疼痛（OA）的新治疗剂。 OA 是一种慢性疾病，随着疾病的发展，患者可以描述不同类型的疼痛，包括疼痛 在体重或关节运动上，休息时疼痛。一些患者显示外围和/或中央的迹象 致敏。令人信服的临床证据表明，OA关节的持续外围输入驱动疼痛 和灵敏度。我们已经开发了鼠DMM（中间弯面板的稳定）来研究 该疾病的慢性性质以及与进行性关节损害相关的不同疼痛行为。 总体目的是表征在感觉神经上的解剖和功能改变 联合的。我们发现，在实验性OA过程中，NAV1.8伤害感受器会经历深刻的 以前未接受的，在各个级别的可塑性（在膝关节，在DRG中和背喇叭中） 精确发展的方式。最近，很明显，可以根据感官神经元根据 分子表达的独特模式是躯体感觉的不同方面的基础。具体来说， NAV1.8神经元包括不同的功能子集，包括热敏感的TRPV1神经元， 机械敏感的MRGPRD C纤维，Th+ C-LOW阈值机械感受器（C-LTMR）和无声CHRNA3 纤维。与OA疼痛的潜在相关性的另一个子集是TRKA+，表达接收器的神经生长 因素。我们假设这些亚群中的特定暂时空间变化介导了 OA进展过程中的疼痛行为。我们的实验计划考虑了研究两个完整的目标（1） 临时和空间贡献（在OA关节中存在哪些神经并在何时何地？）； （2）我们如何针对这些特定的神经元子集来检查对疼痛行为和关节的影响 健康。具体目标1旨在在膝盖神经上定义膝关节神经的临时和空间神经塑性 OA关节病理和疼痛。我们已经使用了各种CRE/FLP驱动程序来生产荧光记者的线条 针对伤害性，机械敏感性和本体感受性（Parvalbumin，PV）DRG的不同子集的小鼠 神经元。我们将使用这些小鼠来定义膝盖神经的解剖和功能变化，并使用 共聚焦和灯表显微镜，体内Ca2+成像以及特定的瞬时化学遗传沉默 神经元子集。特定目标2旨在靶向特定的神经元子集并检查对OA的影响 疾病（疼痛和关节损害），以探讨我们的发现如何转化为OA的新方法 疼痛。我们将确定神经元亚群的慢性化学发生沉默对OA疼痛的影响 和关节损坏。我们还将研究DRG亚群特有的“受体”，以发展 有针对性的治疗干预措施。我们提出，介导的神经元亚群的鉴定 OA疼痛行为将使它们被专门针对疾病的特定阶段，这将 导致新颖，更高效，更安全的治疗方法来解决OA疼痛。