Molecular Pathways of Pain Generation in Osteoarthritis

骨关节炎疼痛产生的分子途径

• 批准号: 9111667
• 负责人: Anne-Marie Malfait
• 金额: $ 42.44万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9111667
• 关键词: ADAMTS; Accounting; Address; Affect; Afferent Neurons; Antibodies; Behavior; Biological Markers; CCL2 gene; Cartilage; Cells; Chronic; Data; Degenerative polyarthritis; Development; Elderly; Experimental Models; Foundations; Fractalkine; Generations; Goals; Grant; Health; Histopathology; Immune; Ipsilateral; Joints; Knee; Knee Osteoarthritis; Knockout Mice; Lead; Ligands; Medical; Methods; Microglia; Modeling; Molecular; Monitor; Movement; Mus; Nervous system structure; Neuraxis; Neuroglia; Neurons; Nociceptors; Operative Surgical Procedures; Organ; Outcome; Pain; Pathway interactions; Pattern; Pattern recognition receptor; Peripheral; Peripheral Nervous System; Population; Progressive Disease; Property; Regulation; Reporter; Role; Secondary Hyperalgesias; Signal Transduction; Source; Spinal Ganglia; Spinal cord posterior horn; Staging; Symptoms; TLR2 gene; TLR4 gene; Testing; Therapeutic; Time; Tissues; Zoledronate; base; bisphosphonate; bone; chemokine; chronic pain; dorsal horn; inhibitor/antagonist; insight; joint injury; longitudinal analysis; mechanical allodynia; molecular marker; mouse model; novel; novel strategies; novel therapeutics; pain behavior; tool; ADAMTS; Accounting; Address; Affect; Afferent Neurons; Antibodies; Behavior; Biological Markers; CCL2 gene; Cartilage; Cells; Chronic; Data; Degenerative polyarthritis; Development; Elderly; Experimental Models; Foundations; Fractalkine; Generations; Goals; Grant; Health; Histopathology; Immune; Ipsilateral; Joints; Knee; Knee Osteoarthritis; Knockout Mice; Lead; Ligands; Medical; Methods; Microglia; Modeling; Molecular; Monitor; Movement; Mus; Nervous system structure; Neuraxis; Neuroglia; Neurons; Nociceptors; Operative Surgical Procedures; Organ; Outcome; Pain; Pathway interactions; Pattern; Pattern recognition receptor; Peripheral; Peripheral Nervous System; Population; Progressive Disease; Property; Regulation; Reporter; Role; Secondary Hyperalgesias; Signal Transduction; Source; Spinal Ganglia; Spinal cord posterior horn; Staging; Symptoms; TLR2 gene; TLR4 gene; Testing; Therapeutic; Time; Tissues; Zoledronate; base; bisphosphonate; bone; chemokine; chronic pain; dorsal horn; inhibitor/antagonist; insight; joint injury; longitudinal analysis; mechanical allodynia; molecular marker; mouse model; novel; novel strategies; novel therapeutics; pain behavior; tool

DESCRIPTION (provided by applicant): Pain is the major symptom in osteoarthritis (OA) and one of the leading causes of impaired mobility in the elderly population in the US. Our lack of understanding of the mechanisms underlying chronic pain in general, and chronic pain associated with OA in particular, accounts for the general ineffectiveness of currently available treatment options. Relief from severe OA pain remains an unmet medical need and a major reason for seeking surgical intervention. The long-term goal of this proposal is to define origins and mechanisms of pain in OA, thus enabling identification of new targets, and development of new therapies and biomarkers for OA pain. Using a sophisticated chronic progressive murine model of knee OA, in combination with state-of-the-art approaches and potent, selective inhibitors, this proposal aims to systematically address the central hypothesis: pathological matrix turnover in the OA joint chronically activates joint nociceptors and causes plasticity changes in the nervous system, resulting in the initiation and the persistence of pain. Aim 1 seeks to define a temporo-spatial role for the chemokines, MCP-1 and fractalkine, in chronic OA pain through longitudinal analysis of changes in the innervating DRG (peripheral nervous system) and dorsal horn (central nervous system) during the course of progressive experimental OA. In order to gain insight into OA pain modulation in the DRG (peripheral nervous system) and transition to the central nervous system, we aim to document molecular markers of activation of cellular subsets in DRG and DH in a temporo-spatial manner over the course of progressive OA. Further, we will test the effect of interfering with MCP-1/CCR2 signaling on pain behaviors and associated pathways. Aim 2 seeks to evaluate the contribution of Pattern Recognition Receptors (PRR) and their ligands (Damage Associated Molecular Patterns, DAMPs) to joint nociceptor activation and OA-associated pain. We will visualize TLR2/4 and RAGE expression on joint nociceptors in the course of progressive knee OA after DMM surgery, using novel Nav1.8-tdTomato reporter mice. We will evaluate the ability of selected DAMPs to activate sensory neurons, using intracellular Ca2+ mobilization and MCP-1 release as outcome markers. In order to assess the contribution of DAMP signaling to pain in this model, we will evaluate pain-related behaviors in novel conditional knock-out mice that lack Myd88 or TLR4 in pain-sensing neurons. Finally, Aim 3 seeks to differentially target pathological components of the OA joint in order to assess effects on pain and associated pathways. We aim to differentially target cartilage or subchondral bone through pharmacological modulation at different times during progressive disease, and monitor pain/pain pathway outcome markers in association with detailed joint histopathology. This will clarify sources and regulation of OA pain in the joint. These aims will lead to considerable gains in understanding how pain is in generated and maintained in OA, and pave the way for a more targeted and safer therapeutic approach.

描述（由申请人提供）：疼痛是骨关节炎（OA）的主要症状，也是美国老年人口流动性受损的主要原因之一。我们对一般慢性疼痛的机制缺乏了解，尤其是与OA相关的慢性疼痛，这是当前可用治疗方案的总体无效性。缓解严重的OA疼痛仍然是未满足的医疗需求，也是寻求手术干预的主要原因。该提案的长期目标是定义OA疼痛的起源和机制，从而可以鉴定新靶标，并开发新的疗法和生物标志物来实现OA疼痛。 Using a sophisticated chronic progressive murine model of knee OA, in combination with state-of-the-art approaches and potent, selective inhibitors, this proposal aims to systematically address the central hypothesis: pathological matrix turnover in the OA joint chronically activates joint nociceptors and causes plasticity changes in the nervous system, resulting in the initiation and the persistence of pain. AIM 1试图通过纵向OA（周围神经系统）和背侧角膜（中枢神经系统）在进行性实验性OA的过程中，通过纵向OA疼痛来定义趋化因子MCP-1和Fractalkine的颞空间作用。为了深入了解DRG（周围神经系统）中的OA疼痛调节，并过渡到中枢神经系统，我们的目标是在渐进的OA过程中以暂时的方式记录DRG和DH的细胞亚群的分子标记。此外，我们将测试干扰MCP-1/CCR2信号对疼痛行为和相关途径的影响。 AIM 2旨在评估模式识别受体（PRR）及其配体（损伤相关的分子模式，湿）对关节伤害感受器激活和OA相关疼痛的贡献。使用新型的NAV1.8-TDTOMATO报告小鼠，我们将在DMM手术后进行性膝关节OA的过程中可视化TLR2/4和在关节伤害感受器上的愤怒表达。我们将使用细胞内CA2+动员和MCP-1释放作为结果标记来评估所选潮湿激活感觉神经元的能力。为了评估该模型中潮湿信号对疼痛的贡献，我们将评估缺乏疼痛感应神经元中缺乏MyD88或TLR4的新型有条件敲除小鼠中疼痛相关的行为。最后，AIM 3试图靶向OA关节的病理成分，以评估对疼痛和相关途径的影响。我们的目的是通过在进行性疾病期间的不同时间进行药理学调节来差异靶向软骨或软骨下骨，并监测与详细的关节组织病理学相关的疼痛/疼痛途径标记。这将阐明关节中OA疼痛的来源和调节。这些目标将导致在了解OA中产生和维持的痛苦方面的巨大收益，并为更具针对性和更安全的治疗方法铺平道路。