The Role of Mechanosensation Pathways in Osteoarthritis Joint Damage and Pain

机械感觉通路在骨关节炎关节损伤和疼痛中的作用

基本信息

批准号：
10861577
负责人：
Rachel Elizabeth Miller
金额：
$ 27.43万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-02 至 2026-02-28
项目状态：
未结题

项目摘要

Project Summary Knee osteoarthritis (OA) is a painful chronic disease affecting 27 million people in the US. Knee OA is characterized by progressive damage and remodeling of all joint tissues. Major hallmarks of OA are joint pain and joint space narrowing on x-ray. Biomechanical and inflammatory factors play an important role in both joint pain and damage, but exactly how these pathways interact and promote mechanical sensitization of sensory neurons is unknown. Recently, we identified the sensory neuron mechanosensitive ion channel Piezo2 as a key contributor to mechanical sensitization in the destabilization of the medial meniscus (DMM) mouse model of OA. In addition, we have demonstrated that NGF-induced joint inflammation is dependent on nociceptor expression of Piezo2, suggesting that Piezo2 signaling may contribute to neuroimmune interactions. Finally, we have demonstrated that macrophage infiltration is a key contributor to the development of mechanical sensitization in OA. Nociceptor signaling helps to facilitate this recruitment of immune cells, but how the Piezo2 pathway is involved is not yet known. Therefore, this supplement represents an expansion of the existing Specific Aim 1 of the parent program. In particular, we will leverage our ongoing studies in nociceptor-specific Piezo2 conditional knock-out mice to now include examination of the neuroimmune changes happening in these mice, in both sexes. This will include using a novel imaging technology – light sheet imaging of cleared knee joint and spinal column/DRG tissue in order to visualize macrophages in these tissues in a volumetric representation. The research outlined here will fill the gap in knowledge by providing information on the interaction of inflammation and mechanical stimuli in producing mechanical sensitization. This proposal aims to answer the questions of: What is the role of Piezo2 in inflammatory mechanical sensitization? And, Can light sheet imaging be used to quantify macrophage numbers in the lumbar DRGs? We hypothesize that mechanical stimuli are necessary for inflammatory mechanical sensitization. In addition, we hypothesize that macrophage recruitment in the DRGs is a fundamental part of mechanical sensitization, and that recruitment will be inhibited by knocking out Piezo2. Successful completion of this supplement will improve our understanding of how nociceptors and immune cells communicate with the help of the Piezo2 pathway to promote mechanical sensitization in OA, which may lead to the identification of novel pathways to target both pain and joint damage therapeutically.

项目概要膝骨关节炎 (OA) 是一种痛苦的慢性疾病，影响着美国 2700 万人。其特征是所有关节组织进行性损伤和重塑，OA 的主要特征是关节疼痛。 X 线显示的关节间隙变窄生物力学和炎症因素在两个关节中都起着重要作用。疼痛和损伤，但这些通路到底如何相互作用并促进感觉的机械敏化最近，我们确定了感觉神经元机械敏感离子通道 Piezo2 是一个关键。导致 OA 内侧半月板 (DMM) 小鼠模型不稳定的机械敏化。此外，我们还证明 NGF 诱导的关节炎症依赖于伤害感受器的表达 Piezo2，表明 Piezo2 信号传导可能有助于神经免疫相互作用。巨噬细胞浸润是机械敏化发展的关键因素 OA。伤害感受器信号传导有助于促进免疫细胞的募集，但 Piezo2 通路是如何发挥作用的？因此，本补充内容是对现有具体目标 1 的扩展。特别是，我们将利用我们在伤害感受器特异性 Piezo2 条件方面正在进行的研究。目前，基因敲除小鼠的研究包括检查这些小鼠（无论性别）中发生的神经免疫变化。这将包括使用一种新颖的成像技术——清除膝关节和脊柱的光片成像柱/DRG 组织，以便以体积表示形式可视化这些组织中的巨噬细胞。这里概述的研究将通过提供有关炎症相互作用的信息来填补知识空白该提案旨在回答以下问题： Piezo2 在炎症机械敏化中的作用是什么？并且，光片成像可以用于吗？量化腰椎 DRG 中的巨噬细胞数量？我们发现机械刺激对于此外，我们还研究了 DRG 中巨噬细胞的募集。机械敏化的基本组成部分，并且通过敲除 Piezo2 可以抑制募集。成功完成本补充课程将提高我们对伤害感受器和免疫细胞如何发挥作用的理解借助 Piezo2 通路进行通信，促进 OA 的机械敏化，这可能会导致确定治疗疼痛和关节损伤的新途径。