Osteoarthritis Progression and Sensory Pathway Alterations

骨关节炎进展和感觉通路改变

• 批准号: 9053984
• 负责人: RICHARD J MILLER
• 金额: $ 42.67万
• 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 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9053984
• 关键词: Afferent Neurons; Agonist; Behavior; C Fiber; CCL2 gene; Capsaicin; Characteristics; Chronic; Clinical; Complex; Degenerative polyarthritis; Disease; Disease Progression; Electrophysiology (science); Elements; Esthesia; Fiber; Goals; Health; Human; Hyperalgesia; Image; Imaging Techniques; Immunohistochemistry; Individual; Joints; Knee; Knee Osteoarthritis; Label; Location; Maintenance; Measurement; Mechanical Stimulation; Mechanics; Medial meniscus structure; Mediating; Medical; Modeling; Mus; Nerve Fibers; Neurons; Neuropathy; Nociception; Nociceptors; Opioid Receptor; Pain; Pathology; Pathway interactions; Patients; Pattern; Peripheral; Pharmacological Treatment; Physiological; Population; Property; Proprioception; Reporting; Secondary Hyperalgesias; Sensory; Signal Transduction; Spinal Ganglia; Staging; Stimulus; Symptoms; Techniques; Technology; Testing; Therapeutic; Time; Tissue Banking; Tissue Banks; Touch sensation; afferent nerve; behavior change; designer receptors exclusively activated by designer drugs; experience; in vivo; in vivo imaging; knee pain; mechanical allodynia; mouse model; novel; pain behavior; promoter; response; selective expression; sensory stimulus; somatosensory; spontaneous pain; vibration

DESCRIPTION (provided by applicant): Osteoarthritis (OA) pain represents an enormous health burden. Patients describe different types of pain over the course of the disease, including pain with mechanical characteristics, neuropathic elements, and intermittent spontaneous pain. Signs of somatosensory disturbances such as mechanical allodynia, loss of proprioception, and vibratory deficits have been reported. Specialized sensory neurons mediate different sensations, including touch, proprioception, vibration, and different types of noxious stimuli. Therefore, we propose that "pain" in OA is more than merely a state where nociceptive neurons in the joint are activated, but rather involves widespread changes in sensory neurons, both in specialized subsets of nociceptive neurons and in non-nociceptive A¿ fibers. Our overall goal is to identify these changes in subsets of neurons in the course of progressive OA. We will use a validated murine model, destabilization of the medial meniscus (DMM) that captures the long-term progression of OA. In this model, pain-dependent behaviors change over time, with knee hyperalgesia and mechanical allodynia presenting early on, while symptoms of ongoing pain are not apparent until 8-16 weeks post DMM. This provides a unique opportunity to longitudinally assess neuronal properties. Our strategy will include three different approaches: (1) To define changes in specific subsets of sensory neurons in dorsal root ganglia (DRG) and joints in the course of knee OA - Subsets of sensory neurons in the joint and innervating DRG, L2-L5, will be documented throughout the progression of disease, through retrograde labeling and immunohistochemistry. Specifically, we will describe the number and location of peptidergic and non-peptidergic C-fibers, of non-nociceptive A¿-fibers, and their expression of markers including CCR2 and Nav1.8. We will validate our findings in a unique human joint tissue bank including patients with meniscal pathology, early and advanced stages of knee OA; (2) To characterize physiological properties of subsets of sensory neurons during initiation and maintenance of OA pain- We will analyse activity of individual subsets of A and C-fibers through electrophysiological recordings on intact DRG, L3/L4, and determine spontaneous activity as well as responses to stimuli including MCP-1, capsaicin, and ATP. We will also employ novel Pirt-GCaMP3 mice to image intracellular Ca2+ in sensory neurons in vivo in response to natural sensory stimuli, including mechanical stimulation applied to the knee; (3) To study the effect of selectively silencing subsets of neurons on different OA pain behaviors - We will test the effect of a selective ¿-opioid receptor on pain-dependent behaviors. We will also employ novel DREADD technology to transiently silence all sensory DRG neurons (using the pan-DRG Advillin promoter) or a subset of nociceptors (using Nav1.8 promoter). The proposal combines neuroanatomical techniques, electrophysiological measurements, in vivo imaging, and state-of-the-art approaches to reversibly silence neurons in order to evaluate changes in populations of sensory neurons that contribute to symptoms in a translational OA model.

描述（由适用提供）：骨关节炎（OA）疼痛代表了巨大的健康伯恩。患者在整个疾病过程中描述了不同类型的疼痛，包括具有机械特征，神经性元素和间歇性赞助疼痛的疼痛。已经报道了诸如机械异常性疾病，本体感受丧失和振动不足之类的体感疾病的迹象。专门的感觉神经元介导了不同的感觉，包括触摸，本体感受，振动和不同类型的有害刺激。因此，我们建议OA中的“疼痛”不仅仅是激活关节中的伤害性神经元的状态，而是涉及感官神经元的宽度变化，无论是在伤害性神经元的专业子集和非吸引性神经元中的专门子集中。我们的总体目标是在进步的OA过程中确定神经元子集的这些变化。我们将使用经过验证的鼠模型，捕获OA的长期进展的中位弯板（DMM）的稳定。在该模型中，疼痛依赖的行为会随着时间的流逝而变化，膝关节痛觉过敏和机械性异常性症早期出现，而直到DMM后8-16周才会出现持续疼痛的症状。这为纵向评估神经元特性提供了独特的机会。我们的策略将包括三种不同的方法：（1）定义背侧根神经节（DRG）中感觉神经元的特定子集的变化以及膝关节OA过程中的关节 - 关节中的感觉神经元的子集，并支配DRG，L2 -L5，通过逆转疾病，通过逆转的疾病，通过逆转，通过逆转，通过逆转和Imminminmuno offraide和Imminmunoy Orchemering和Imminmuno Hormetersymisterics offrape。具体而言，我们将描述非感染者a。纤维的胡椒和非肽吉式C纤维的数量和位置及其在内的标记（包括CCR2和NAV1.8）的表达。我们将在独特的人类关节组织库中验证我们的发现，包括半月板病理，膝盖OA的早期和晚期阶段； （2）在OA疼痛的主动和维持过程中表征感觉神经元子集的物理特性 - 我们将通过电生理学分析A和C纤维的单个子集的活性 对完整DRG，L3/L4的记录，并确定赞助活动以及对包括MCP-1，辣椒素和ATP在内的刺激的反应。我们还将使用新型的PIRT-GCAMP3小鼠在体内对自然感觉刺激的感觉神经元中的细胞内Ca2+成像，包括施加在膝盖上的机械刺激； （3）研究神经元选择性沉默子集对不同OA疼痛行为的影响 - 我们将测试选择性»阿片类受体对疼痛依赖性行为的影响。我们还将采用新颖的Dreadd技术来暂时沉默所有感觉DRG神经元（使用PAN-DRG Advillin启动子）或一部分伤害感受器（使用NAV1.8启动子）。该提案结合了神经解剖技术，电生理测量，体内成像和最新方法，以可逆地沉默神经元，以评估有助于翻译OA模型中符号的感觉神经元种群的变化。