Neural Architecture of the Murine and Human Temporomandibular Joint

小鼠和人类颞下颌关节的神经结构

• 批准号: 10608491
• 负责人: Dawen Cai
• 金额: $ 573.45万
• 依托单位: DUKE UNIVERSITY
• 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/10608491
• 关键词: Address; Adult; Affect; Afferent Neurons; Anatomy; Architecture; Area; Arthralgia; Atlases; Bar Codes; Bioinformatics; Biology; Calcium; Characteristics; Chronic; Clinical; Clinical Data; Clinical Research; Data Set; Development; Dimensions; Disease; Dyes; Esthesia; Genetic; Genetic Techniques; Goals; Health; Human; Image; In Situ Hybridization; Individual; Injections; Joints; Knowledge; Label; Lead; Light; Link; Magnetic Resonance Imaging; Maps; Mediating; Michigan; Microscopy; Mission; Modeling; Molecular; Morbidity - disease rate; Mus; Nervous system structure; Neurologic; Neurons; Nociception; Nociceptors; Online Systems; Operative Surgical Procedures; Organ Donor; Orofacial Pain; Pain; Pain Origin; Pain Research; Pathogenesis; Patients; Peripheral; Phenotype; Physiological; Play; Prevalence; Property; Public Health; Publications; Reporter; Research; Research Personnel; Role; School Dentistry; Sensory; Sensory Ganglia; Small Nuclear RNA; Structure of trigeminal ganglion; System; Temporomandibular Joint; Temporomandibular Joint Disorders; Temporomandibular joint disorder pain; Testing; Therapeutic Intervention; Tissues; Tracer; United States National Institutes of Health; Universities; Viral; Visualization; Work; adeno-associated viral vector; behavioral phenotyping; biobank; biopsychosocial; cell type; cellular targeting; chronic pain; clinical phenotype; cohort; data dissemination; data visualization; effective therapy; experimental study; functional plasticity; genetic approach; human tissue; in vivo; interest; medical schools; mouse model; multidisciplinary; nerve supply; neural circuit; neurophysiology; novel; novel therapeutic intervention; orofacial; pain reduction; relating to nervous system; repository; sensor; somatosensory; spatiotemporal; targeted treatment; tissue mapping; tool; transcriptomics; user-friendly

ABSTRACT: Temporomandibular disorders (TMDs) are the most common form of chronic orofacial pain, affecting 5% of U.S. adults. Despite substantial clinical and research interest in this area, progress to identify and target pathophysiological mechanisms underlying TMDs has been slow. This lackluster progress is owed in large part to our relatively primitive understanding of the basic neuroanatomical, molecular, and physiological features of sensory afferents present within the temporomandibular joint (TMJ) tissues. The Restoring Joint Health and Function to Reduce Pain (RE-JOIN) Consortium seeks to address this knowledge gap through the formation of interdisciplinary teams which can define the innervation of articular and peri-articular tissues that collectively make up the jaw joint. To this end, project MPIs Donnelly (Duke University School of Medicine), Emrick (University of Michigan School of Dentistry), and Cai (University of Michigan Medical School) have partnered together to comprehensively map the peripheral neural architecture of the tissues of the temporomandibular joint (TMJ) in mice and humans. Using MRI-guided stereotactic approaches to deliver retrograde dyes and viral tracers with spatiotemporal precision, we will investigate the molecular properties of peripheral sensory neurons which innervate distinct tissues within the murine TMJ in both steady-state and TMD conditions, using this information to build new intersectional genetic mouse models to permit whole-TMJ mapping using lightsheet microscopy. In addition, using intersectional genetic approaches in conjunction with chemogenetics, in vivo Ca2+ imaging, and behavioral phenotyping, we will characterize the physiological/functional properties of TMJ-innervating sensory neurons, allowing us to identify neuronal subpopulations which contribute to chronic pain in TMD. To address the translational gap between mice and humans, we will establish a biobank of TMJ tissues from TMD-free healthy human donors and from a cohort of clinically-phenotyped patients pursuing elective TMJ surgeries to manage chronic intraarticular TMD conditions, followed by quantitative analysis of peripheral afferent subtypes across TMJ tissues in each cohort. Finally, we will build a free, user-friendly web- based platform to integrate the resulting transcriptomic, functional, and macroscopic imaging datasets to permit widespread dissemination of these data, which we anticipate will yield a working model of the sensory architecture of the temporomandibular joint tissues in mice and humans, including alterations in TMDs compared to steady-state conditions.

抽象的： 颞下颌关节紊乱病 (TMD) 是最常见的慢性口面部疼痛，影响 5% 的人 美国成年人。尽管对该领域有大量的临床和研究兴趣，但在识别和靶向方面取得了进展 TMD 的病理生理机制进展缓慢。这种乏善可陈的进展在很大程度上是由于 我们对基本神经解剖学、分子和生理学特征的相对原始的理解 感觉传入存在于颞下颌关节 (TMJ) 组织内。恢复关节健康和 减少疼痛功能 (RE-JOIN) 联盟寻求通过组建 跨学科团队可以定义关节和关节周围组织的神经支配，这些组织共同 弥补下颌关节。为此，MPIs Donnelly 项目（杜克大学医学院），Emrick （密歇根大学牙科学院）和蔡（密歇根大学医学院）合作 共同全面绘制颞下颌组织的周围神经结构图 小鼠和人类的关节（TMJ）。使用 MRI 引导的立体定向方法递送逆行染料和病毒 具有时空精度的示踪剂，我们将研究外周感觉的分子特性 在稳态和 TMD 条件下神经支配小鼠 TMJ 内不同组织的神经元，使用 这些信息可用于构建新的交叉遗传小鼠模型，以允许使用以下方法进行全颞下颌关节图谱绘制 光片显微镜。此外，使用交叉遗传学方法与化学遗传学相结合， 体内 Ca2+ 成像和行为表型，我们将表征其生理/功能特性 颞下颌关节支配的感觉神经元，使我们能够识别导致慢性疼痛的神经元亚群 TMD 痛苦。为了解决小鼠和人类之间的翻译差距，我们将建立 TMJ 生物库 来自无 TMD 的健康人类捐赠者和一组临床表型患者的组织 选择性 TMJ 手术来治疗慢性关节内 TMD 病症，然后进行定量分析 每个队列中颞下颌关节组织的外周传入亚型。最后，我们将建立一个免费的、用户友好的网络- 基于平台来整合所得的转录组、功能和宏观成像数据集，以允许 这些数据的广泛传播，我们预计这将产生感官的工作模型 小鼠和人类颞下颌关节组织的结构，包括 TMD 的改变 与稳态条件相比。