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.

对颞下颌关节传入神经突的功能、类型、分布和可塑性的认识 关节（TMJ）组织是需要了解控制发展的潜在机制， 颞下颌关节紊乱病（TMJD）疼痛。本提案的目的是弥补这一关键差距， 通过全面阐明的功能，类型，神经解剖分布和可塑性的知识， 支配咬肌（MM）和翼外肌的肌肉、肌腱和筋膜的三叉神经（TG）神经元 (LPM)结果表明，男性、女性和老年人颞下颌关节髁突周围的软骨、关节囊和韧带 小鼠、灵长类动物和人类，有和没有TMJD疼痛状况。为支持这项建议，我们 证明TMJ组织由具有独特和不同性质的三叉神经（TG）神经元支配， 与先前描述的TG和背根神经节（DRG）相比， 神经元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 将映射的位置和阐明的表型和可塑性的TG神经元支配颞下颌关节组织， 患有和不患有TMJD疼痛病症的雄性、雌性和老年小鼠、灵长类动物和人类。我们也期待 TMJD患者TMJ组织中的候选治疗靶点鉴定，这可能最终导致可能的 TMJD的新疗法这项研究将在四个相互关联但又相互独立的目标下进行。目标1确定 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 有和没有TMJD的小鼠。目的2：研究颞下颌关节紊乱病（TMJD）小鼠颞下颌关节的传入神经纤维分布。 目的3定位支配颞下颌关节组织的三叉神经节神经元突起的位置，明确三叉神经节神经元的表型和可塑性 在有和没有TMJD的非人灵长类动物（NHP）中。目的4研究颞下颌关节组织神经和细胞的可塑性， TMJD患者。这项工作产生的大量数据将产生重大的积极影响， 实现了RE-JOIN程序的大多数目标，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表征;（3） 在雄性、雌性和老年小鼠、灵长类动物和人类中鉴定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;以及（5）增加研究 通过验证灵长类动物和人类组织中TMJD小鼠模型的数据，拟议 实验将创建大型、综合、注释数据集和元数据，并开发先进的方法， 这将与进行类似研究的研究界分享。