Innervation of the knee and TMJ

RE-JOIN联盟的首要目标是确定神经元是如何介导 慢性关节疼痛支配不同的关节和关节周围组织，重点是膝关节 和颞下颌关节（TMJ）。随着对不同的神经系统 亚型通过关节分布，以及这些亚型如何随年龄和疾病而变化，新的 可以开发治疗以减轻慢性关节疼痛的沉重负担。为了实现这一目标， 我们的团队将专注于推进我们对膝关节病理-疼痛关系的理解， 和颞下颌关节的神经追踪，三维成像，和评估的专业知识相结合， 慢性关节疼痛和残疾。我们的提案汇集了一个高度协作的团队， 横跨基础科学和临床研究，在膝盖和颞下颌关节方面拥有丰富的经验， 使我们能够评估神经支配网络中的共享与联合特异性变化， 慢性关节疼痛的发展。具体来说，我们的团队将首先使用神经示踪染料来识别 背根神经节和三叉神经节中的细胞体投射到肌肉，骨骼， 或关节内关节组织。然后，这些神经元将被评估其功能， 使用单细胞RNA-Seq.通过重叠神经 功能与基因表达，我们将确定启动子的目标和设计腺相关 病毒（AAV）载体，以在这些靶标表达的同时产生荧光标记。 重要的是，这种方法将使我们能够开发基于AAV的示踪剂，用于特定的功能性神经细胞。 亚型，以及联合收割机将功能亚型的传统标志物与任何新鉴定的 描述神经元如何随年龄、性别和骨关节炎（OA）严重程度而变化的标志物。 使用这些示踪剂，我们将评估整个过程中功能性神经亚型的分布。 关节（包括骨、软骨、滑膜、关节囊、韧带、肌腱、筋膜和肌肉） 以及这些神经支配网络如何随年龄、性别和OA严重程度而变化。而且这些 示踪剂将被用来评估关节神经支配如何适应两个神经的应用后， 用于缓解膝关节和颞下颌关节疼痛的消融技术。评价我们的临床意义 临床前研究，将在从患者收集的组织中评估神经支配变化 接受膝关节或颞下颌关节的全关节置换术。在我们所有的研究中，联合神经支配 结合关节疼痛和残疾的详细分析。在啮齿类动物中，这些分析将包括 详细的行为特征;在患者中，这些分析将包括定量感觉 测试和其他关节功能评估。结合起来，这种方法将使我们能够评估 从临床前模型到临床，与关节神经支配相关的病理-疼痛关系。

The over-arching goal for the RE-JOIN Consortium is to define how the neurons that mediate chronic joint pain innervate different articular and peri-articular tissues, with a focus on the knee and temporomandibular joint (TMJ). With an improved understanding of how different neural subtypes distribute through the joint and how these subtypes change with age and disease, new therapies can be developed to reduce the heavy burden of chronic joint pain. To achieve this goal, our team will focus on advancing our understanding of pathology-pain relationships in the knee and TMJ by combining expertise in neural tracing, 3-dimensional imaging, and evaluations of chronic joint pain and disability. Our proposal brings together a highly collaborative team that spans basic science and clinical research with extensive experience in both the knee and TMJ, allowing us to evaluate shared vs. joint-specific shifts in innervation networks and the development of chronic joint pain. Specifically, our team will first use neural tracing dyes to identify the cell bodies in the dorsal root ganglia and trigeminal ganglia that project to the muscle, bone, or intra-articular joint tissues. These neurons will then be evaluated for their function using electrophysiologic tests and their transcriptome using single cell RNA-Seq. By overlapping neural function with gene expression, we will identify promoter targets and design adeno-associated virus (AAV) vectors to produce fluorescent labels alongside the expression of these targets. Importantly, this approach will allow us to develop AAV-based tracers for specific functional neural subtypes, as well as combine traditional markers of functional subtypes with any newly identified markers that describe how the neuron changes with age, sex, and osteoarthritis (OA) severity. Using these tracers, we will then evaluate the distribution of functional neural subtypes throughout the joint (including bone, cartilage, synovium, joint capsule, ligament, tendon, fascia, and muscle) and how these innervation networks change with age, sex, and OA severity. Moreover, these tracers will be used to evaluate how joint innervation adapts following the application of two neural ablation techniques for pain relief in the knee and TMJ. To evaluate the clinical significance of our preclinical studies, innervation changes will be assessed in tissues collected from patients undergoing total joint replacement of the knee or TMJ. In all of our studies, joint innervation will be paired with detailed analyses of joint pain and disability. In rodents, these analyses will include detailed behavioral characterizations; in patients, these analyses will include quantitative sensory tests and other assessments of joint function. Combined, this approach will allow us to evaluate pathology-pain relationships related to joint innervation from the preclinical model to the clinic.