Comprehensive functional phenotyping of trigeminal neurons innervating temporomandibular joint (TMJ) tissues in male female and aged mice primates and humans with and without TMJ disorders (TMJD)

对患有或不患有颞下颌关节疾病 (TMJD) 的雄性、雌性和老年小鼠灵长类动物以及人类中支配颞下颌关节 (TMJ) 组织的三叉神经元的综合功能表型分析

• 批准号: 10608279
• 负责人: ARMEN N AKOPIAN
• 金额: $ 469.81万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 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/10608279
• 关键词: 3-Dimensional; Ablation; Address; Afferent Neurons; Animal Model; Antibodies; Back; Behavioral; Biopsy; Callithrix; Cartilage; Cells; Communities; Computer software; Data; Data Set; Development; Diagnosis; Disease model; Diskectomy; Electrophysiology (science); Fascia; Female; Fiber; Fluorescent Dyes; Goals; Human; IACUC; Immunohistochemistry; Joint Capsule; Knowledge; Lateral; Lead; Ligaments; Light; Location; Manuals; Maps; Mediator of activation protein; Metadata; Microscopy; Modality; Molecular Profiling; Mus; Muscle; Myofascial Pain Syndromes; Nerve Tissue; Neurites; Neurons; Pain; Pain Disorder; Pain-Free; Patients; Phenotype; Physiological; Prevention; Primates; Property; Protocols documentation; Pterygoid Muscle; Publishing; Reporter; Research; Resolution; Sensory; Spinal Ganglia; Techniques; Temporomandibular Joint; Temporomandibular Joint Disorders; Temporomandibular joint disorder pain; Tendon structure; Tissues; Translating; Trigeminal System; Visualization; Work; aged; base; candidate marker; clinical development; clinically relevant; data harmonization; experience; experimental study; human tissue; improved; in vivo; in vivo imaging; male; mouse model; multidimensional data; multidisciplinary; nerve supply; new therapeutic target; nonhuman primate; novel; pain patient; programs; receptor; single cell sequencing; therapeutic candidate; therapeutic target; tibialis anterior muscle; tool; transcriptome sequencing

The knowledge of the function, types, distributions, and plasticity of afferent neurites innervating temporomandibular joint (TMJ) tissues is needed to understand the underlying mechanisms controlling the development of temporomandibular joint disorder (TMJD) pain. The objective of this proposal is to address this critical gap in knowledge by comprehensively elucidating the functions, types, neuroanatomical distributions, and plasticity of trigeminal (TG) neurons innervating the muscles, tendons, and fascia of the masseter (MM) and lateral pterygoid (LPM) muscles, as well as the cartilage, joint capsule, and ligament around TMJ condyle in male, female and aged mice, primates, and humans with and without TMJD pain conditions. In support of this proposal, we have demonstrated that TMJ tissues are innervated by trigeminal (TG) neurons with unique and distinct properties, distributions and molecular signatures compared to previously described TG and dorsal root ganglia (DRG) neurons. Based on supporting data and the expertise of our multi-disciplinary team, we anticipate that this project will map the location and elucidate the phenotype and plasticity for TG neurons innervating TMJ tissues in male, female, and aged mice, primates and humans with and without TMJD pain conditions. We also expect candidate therapeutic target identification in TMJD patients’ TMJ tissues, which could ultimately lead to possible new treatments for TMJD. This study will be conducted in four interconnected yet independent aims. Aim 1 identifies the molecular signature, function and plasticity of TG neurons innervating TMJ tissues in male, female and aged mice with and without TMJD. Aim 2 maps afferent neurites innervating TMJ tissues in mice with and without TMJD. Aim 3 maps the location of neurites and define the phenotype and plasticity of TG neurons innervating TMJ tissues in non-human primates (NHP) with and without TMJD. Aim 4 examines TMJ tissue nerves and cell plasticity in TMJD patients. Substantial amount of data generated by this work will have a substantial positive impact by achieving most objectives of the RE-JOIN program, including (1) mapping the location of the afferent neurites in TMJ tissues; (2) phenotyping and functionally characterizing TG neurons innervating a variety of TMJ tissues; (3) identifying TMJD-induced plasticity of these TG neurons in male, female and aged mice, primates and humans; (4) identifying novel candidate therapeutic targets in biopsies from TMJD patients; and (5) increasing study translatability by validating data from TMJD mouse models in primate and human tissues. The proposed experiments will create large, integrated, annotated datasets and metadata and develop advanced approaches, which will be shared with the research community conducting similar studies.

了解支配颞下颌的传入神经突的功能、类型、分布和可塑性 需要关节（TMJ）组织来了解控制发育的潜在机制 该提案的目的是解决颞下颌关节紊乱病 (TMJD) 疼痛的这一关键差距。 通过全面阐明神经元的功能、类型、神经解剖学分布和可塑性来获得知识 三叉神经 (TG) 神经元支配咬肌 (MM) 和翼外肌的肌肉、肌腱和筋膜 (LPM) 肌肉，以及男性、女性和老年人颞下颌关节髁周围的软骨、关节囊和韧带 患有或不患有颞下颌关节紊乱病（TMJD）疼痛的小鼠、灵长类动物和人类为了支持这一提议，我们有： 证明颞下颌关节组织由具有独特和独特特性的三叉神经元 (TG) 神经支配， 与之前描述的 TG 和背根神经节 (DRG) 相比的分布和分子特征 基于支持数据和我们多学科团队的专业知识，我们预计该项目 将绘制支配 TMJ 组织的 TG 神经元的位置并阐明其表型和可塑性 我们还预期有或没有 TMJD 疼痛的雄性、雌性和老年小鼠、灵长类动物和人类。 TMJD 患者 TMJ 组织中候选治疗靶点的识别，最终可能导致 这项研究将针对四个相互关联但独立的目标进行。 男性、女性和老年人支配颞下颌关节组织的 TG 神经元的分子特征、功能和可塑性 Aim 2 绘制了患有和不患有 TMJD 的小鼠中支配 TMJ 组织的传入神经突。 目标 3 绘制神经突的位置并定义支配 TMJ 组织的 TG 神经元的表型和可塑性 在患有或不患有 TMJD 的非人类灵长类动物 (NHP) 中，目的 4 检查 TMJ 组织神经和细胞可塑性。 这项工作产生的大量数据将对 TMJD 患者产生巨大的积极影响。 实现 RE-JOIN 计划的大部分目标，包括 (1) 绘制传入神经突的位置 TMJ 组织；(2) 支配各种 TMJ 组织的 TG 神经元的表型和功能特征； 鉴定雄性、雌性和老年小鼠、灵长类动物和人类中 TMJD 诱导的这些 TG 神经元的可塑性 (4) 从 TMJD 患者的活检中确定新的候选治疗靶点；(5) 加强研究； 通过验证灵长类和人体组织中 TMJD 小鼠模型的数据来提高可翻译性。 实验将创建大型、集成、带注释的数据集和元数据，并开发先进的方法， 这将与进行类似研究的研究界共享。