Piezo2-mediated neuroplasticity in osteoarthritis

Piezo2 介导的骨关节炎神经可塑性

• 批准号: 10752471
• 负责人: Natalie Adamczyk
• 金额: $ 4.77万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752471
• 关键词: Ablation; Activities of Daily Living; Afferent Neurons; Animal Behavior; Animal Model; Arthralgia; Arthritis; Attenuated; Behavior; Biological Assay; Blood; Bradykinin; Cartilage; Cells; Chronic; Combined Modality Therapy; Communication; Complex; Critical Thinking; Data; Degenerative polyarthritis; Development; Disease; Enzyme-Linked Immunosorbent Assay; Exhibits; Experimental Designs; Flow Cytometry; Genetic; Goals; Grant; High Prevalence; Histology; Human; Hyperalgesia; Image; Immune; In Vitro; Induction of Apoptosis; Inflammation; Inflammation Mediators; Inflammatory; Injections; Ion Channel; Joints; Knee; Knee joint; Knock-out; Knowledge; Learning; Leg; Link; Macrophage; Measurement; Mechanical Stimulation; Mechanics; Medial; Medial meniscus structure; Mediating; Mediator; Modeling; Molecular; Movement; Mus; Nature; Nerve; Nerve Growth Factors; Neuroimmune; Neurologic; Neuronal Plasticity; Neurons; Neurosciences; Nociceptors; Non-Steroidal Anti-Inflammatory Agents; Operative Surgical Procedures; Outcome; Pain; Pain management; Pathology; Pathway interactions; Patients; Peptide Hydrolases; Persistent pain; Phenocopy; Piezo 2 ion channel; Play; Prevention; Process; Production; Quality of life; Reporting; Research; Role; Route; Spinal Ganglia; Spinal cord posterior horn; Swelling; Synovial Fluid; Synovial Membrane; Synovitis; System; Techniques; Testing; Therapeutic; Therapeutic Intervention; Training; Weight; Weight-Bearing state; attenuation; career; chronic pain; cytokine; disability; disabling symptom; effective therapy; effectiveness evaluation; immune activation; in vivo calcium imaging; joint inflammation; joint injury; joint loading; mechanical load; mechanical signal; mechanical stimulus; mechanotransduction; mouse model; neuroinflammation; novel; osteoarthritis pain; pain behavior; prevent; recruit; skills; transcriptome sequencing; transcriptomics

Project Summary Despite the high prevalence of chronic pain and disability due to osteoarthritis (OA), there currently is no effective treatment available to stop progression or manage pain long term. Patients often report ceasing activities they found previously enjoyable or avoiding activities required for daily living due to the highly mechanosensitive nature of OA pain. Our understanding of OA has evolved from a wear and tear mindset to a complex disease state involving the immune and neurological systems, indeed there is an increase in immune cells and inflammatory mediators within the synovial fluid of humans and mice. Further in mice we see an increase in macrophages in knee innervating dorsal root ganglia (DRG); prevention of macrophage recruitment, by macrophage depletion or nociceptor silencing, has shown promise in reducing OA pain like behaviors. Interestingly, mice with Piezo2, a mechanically activated ion channel, knocked out from nociceptors demonstrate a reduction in pain behavior in two models of joint pain and are protected from joint swelling. Within animal modeling of OA there is evidence of altered neuroplasticity and sensitization that is attenuated by anti-nerve growth factor (NGF) therapy and through inhibition of Piezo2 suggesting an interplay between mechanical stimuli and inflammation in neuroplasticity. Unloading has been shown to silence mechanical signal transduction, decrease the expression of harmful proteases in the knee and is more effective in reducing synovitis than combination treatment with NSAIDs. However, no study has assessed the effect of unloading on pain associated neuroplasticity. We believe that mechanical signaling is a key player in macrophage recruitment and sensitization in OA, specifically through Piezo2. Therefore, our central hypothesis is: mechanical stimuli are necessary for joint neuroplasticity and inflammatory mechanical sensitization and by inhibiting mechanotransduction we will effectively reduce immune cell recruitment, abhorrent neuroplasticity and thus pain. Aim 1 will assess the effectiveness of inhibition of mechanical stimuli through Piezo2CKO in reducing immune cell recruitment to the knee and DRG. Aim 2 will tease apart the interplay of mechanical loading and inflammation in pain associated neuroplasticity by mechanically unloading mice to determine if altered neuroplasticity occurs under experimental pain conditions. This project will provide me the opportunity to learn new skills (flow cytometry, in vivo calcium imaging, sequencing) and develop novel techniques. I will also be given the opportunity to enhance skillsets required to achieve my career goals i.e. experimental design, scientific communication, critical thinking etc. Completion of the proposed project will increase our understanding of the interplay of mechanical information and immune cell dynamics in pain development and open the doors to routes of selective therapeutic intervention.

项目摘要 尽管由于骨关节炎(OA)而导致的慢性疼痛和残疾的发病率很高，但目前没有 有效的治疗方法可以阻止病情发展或长期控制疼痛。患者经常报告停止 他们认为以前是愉快的活动或避免日常生活所需的活动，因为高度 骨性关节炎疼痛的机械敏感性。我们对办公自动化的理解已经从一种磨损的心态演变成一种 涉及免疫和神经系统的复杂疾病状态，确实存在免疫力的增加 人类和小鼠关节液中的细胞和炎症介质。在老鼠身上，我们看到了一种 膝关节支配背根神经节的巨噬细胞增多；巨噬细胞的预防 通过巨噬细胞耗尽或伤害性感受器沉默进行的募集，在减轻骨性关节炎疼痛方面显示出了希望 行为。有趣的是，带有Piezo2的小鼠，一种机械激活的离子通道，从伤害性感受器中被淘汰 在两种关节疼痛模型中表现出疼痛行为的减少，并防止关节肿胀。 在OA的动物模型中，有证据表明神经可塑性和敏感化的改变是减弱的 通过抗神经生长因子(NGF)治疗和通过抑制Piezo2提示 神经可塑性中的机械刺激和炎症。卸货已被证明可以使机械静音 信号转导，减少膝关节中有害蛋白的表达，更有效地减少 滑膜炎优于非类固醇抗炎药联合治疗。然而，还没有研究评估卸货对 疼痛相关的神经可塑性。我们认为机械信号在巨噬细胞中起着关键作用。 特别是通过Piezo2，在OA中进行招募和敏感化。因此，我们的中心假设是： 机械刺激是关节神经可塑性和炎性机械敏化所必需的，并通过 抑制机械转导会有效降低免疫细胞募集、可恶的神经可塑性 也因此带来痛苦。目的1将评估通过Piezo2CKO抑制机械刺激的有效性 减少免疫细胞向膝部和背根节的募集。目标2将梳理出机械设备之间的相互作用 通过机械卸载小鼠来确定疼痛相关神经可塑性中的负荷和炎症 在实验性疼痛条件下，神经可塑性发生改变。这个项目将为我提供一个机会 学习新技术(流式细胞术、体内钙成像、测序)并开发新技术。这就做 也有机会提高实现我的职业目标所需的技能，即实验设计， 科学沟通、批判性思维等。拟议项目的完成将增加我们的 了解机械信息和免疫细胞动力学在疼痛发生和发展中的相互作用 打开选择治疗干预途径的大门。