Innervation of the knee and TMJ

膝关节和颞下颌关节的神经支配

• 批准号: 10608403
• 负责人: Kyle D Allen
• 金额: $ 587.9万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-23 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608403
• 关键词: 3-Dimensional; Ablation; Age; Anatomy; Arthralgia; Basic Science; Behavior; Behavioral; Biological Assay; Biological Factors; Bite; Cartilage; Cells; Chronic; Classification; Clinic; Clinical; Clinical Research; Complex; Data; Databases; Degenerative polyarthritis; Dependovirus; Development; Development Plans; Disease; Dyes; Electrophysiology (science); Emerging Technologies; Fascia; Female; Fibrinogen; Gene Expression; Genes; Goals; Human; Image; Image Analysis; Joint Capsule; Joints; Knee; Knee Osteoarthritis; Knee joint; Label; Ligaments; Maps; Measures; Mediating; Modeling; Muscle; Nature; Nerve; Nervous system structure; Neurons; Neurophysiology - biologic function; Operative Surgical Procedures; Pain; Pain Measurement; Pathology; Patient Recruitments; Patients; Pattern; Phenotype; Positioning Attribute; Pre-Clinical Model; Rattus; Replacement Arthroplasty; Resources; Rodent; Sensory; Series; Severities; Signal Transduction; Spinal Ganglia; Stains; Structure of trigeminal ganglion; Symptoms; Synovial Membrane; System; Techniques; Temporomandibular Joint; Temporomandibular Joint Disorders; Temporomandibular joint osteoarthritis; Tendon structure; Testing; Tissues; Tracer; Translating; adeno-associated viral vector; age related; arthropathies; base; bone; clinical pain; clinically relevant; clinically significant; design; disability; experience; histological slides; human tissue; improved; joint function; joint injury; male; meniscus injury; nerve supply; novel strategies; novel therapeutics; pain relief; pre-clinical; preclinical study; promoter; relating to nervous system; response; sex; single-cell RNA sequencing; technology development; transcriptome; transcriptome sequencing; transcriptomics

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.

重新加入财团的整个目标是定义如何介导的神经元 慢性关节疼痛支配不同的关节和关节周围组织，重点是膝盖 和颞下颌关节（TMJ）。有了改善对不同神经的了解 亚型通过关节分布以及这些亚型如何随着年龄和疾病的变化，新的变化 可以开发疗法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促进我们对膝盖病理学关系的理解 和TMJ通过结合神经追踪，三维成像的专业知识以及评估 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 跨越基础科学和临床研究，在膝盖和TMJ方面具有丰富的经验， 允许我们评估神经网络中的共享与特定于联合的转移 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跟踪染料来识别 背侧根神经节和三叉神经节中的细胞体，将肌肉，骨骼，骨骼， 或关节内关节组织。然后，将对这些神经元的功能进行评估 使用单细胞RNA-Seq进行电生理测试及其转录组。通过重叠的神经 具有基因表达的功能，我们将识别启动子目标并设计腺相关 病毒（AAV）向量与这些靶标的表达同时产生荧光标签。 重要的是，这种方法将使我们能够为特定功能神经开发基于AAV的示踪剂 亚型，以及将功能亚型的传统标记与任何新鉴定的 描述神经元如何随着年龄，性别和骨关节炎（OA）严重程度而变化的标记。 然后，我们将在整个过程中评估功能神经亚型的分布 关节（包括骨骼，软骨，滑膜，关节囊，韧带，肌腱，筋膜和肌肉） 以及这些神经网络如何随着年龄，性别和OA的严重性而变化。而且，这些 示踪剂将用于评估两个神经后如何适应关节神经 减轻膝盖和TMJ疼痛的消融技术。评估我们的临床意义 临床前研究，将在患者收集的组织中评估神经变化 进行膝盖或TMJ的总接头更换。在我们的所有研究中，联合神经将 与关节疼痛和残疾的详细分析相结合。在啮齿动物中，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 联合功能的测试和其他评估。合并，这种方法将使我们能够评估 病理学呼吸关系与从临床前模型到诊所的关节神经有关。