Regulation of masticatory myalgia development by distinct trigeminal neuron subtypes innervating masseter muscle

支配咬肌的不同三叉神经元亚型对咀嚼肌痛发展的调节

基本信息

批准号：
10678376
负责人：
Karen Lindquist
金额：
$ 4.14万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10678376
关键词：
Acceleration Affect Afferent Neurons Anatomy Basic Science Behavioral Assay Bite Bite Force Cardiovascular system Cells Cessation of life Characteristics Chronic Clinical Complex Data Deglutition Development Devices Disease Electrophysiology (science)Epidemic Fiber Foundations Functional disorder Gene Expression Profile Genetic Goals Grant Health Hypersensitivity Injury Investigation Kidney Knowledge Learning Machine Learning Masseter Muscle Mastication Masticatory muscles Measures Mechanics Mechanoreceptors Mediating Modality Modeling Mus Muscle Development Musculoskeletal Pain Myalgia Neurites Neuroglia Neurologic Neuronal Plasticity Neurons Opioid Orofacial Pain Overdose Pain Pain management Peripheral Persons Piezo 2 ion channel Prevention Primates Property Published Comment Regulation Research Risk Factors Role Scientist Smiling Substance abuse problem Temporomandibular Joint Disorders Testing Time Training Transgenic Mice Translational Research Trigeminal System Work base behavioral phenotyping burden of illness candidate marker career chronic pain clinically relevant collagenase defined contribution designer receptors exclusively activated by designer drugs disability genetic signature in vivo imaging masticatory myalgia mechanical stimulus mouse model multidisciplinary muscular structure novel therapeutic intervention opioid overuse orofacial pain relief patch clamp prevent receptor response single cell analysis single cell sequencing single-cell RNA sequencing social therapeutic target

项目摘要

Project Summary/Abstract Temporomandibular disorders affecting the muscles of mastication (TMDM) are the most prevalent group of chronic orofacial pain conditions. TMDM chronic pain arising from the masseter muscle (MM) is common. My long-term goals are to elucidate the underlying mechanisms controlling the development of TMDM chronicity and to understand the function and TMDM-induced plasticity of neurons innervating the MM. I recently demonstrated that the MM of mice and primates is predominantly innervated by myelinated A-fibers with unique electrophysiological characteristics and receptor compositions. To further unravel the identity of these neurons we performed single-cell RNA sequencing and have identified unique types of neurons that innervate the MM. Selective markers can be used for specific manipulation of activities for these neuronal clusters. The main objective of this proposal is to define the contribution of MM innervating TG neuronal groups in the progress of TMDM chronicity. The central hypothesis of this proposal is that neurons innervating the MM have specialized neuron type-dependent distinct contributions in the development of TMDM chronicity and undergo unique plasticity of mechano-gated responses during TMDM. To test this hypothesis, our newly developed clinically relevant model of chronic masseteric muscle pain (myalgia) in mice will be employed. Aim 1 will define the contribution of different types of neurons innervating the MM in the development of TMDM by measuring mechanical hypersensitivity using grimace scores, von Frey, conditioned place avoidance, and bite force. To do this, we will exploit the availability of transgenic mouse lines and our single-cell data for manipulation of neuronal activities for specific groups of TG neurons innervating MM. Designer Receptors Exclusively Activated by Designer Drugs (DREADD) will be used to inhibit neuronal activities. Aim 2 will examine the impact of TMDM on mechano-gated responses in neuronal groups innervating the MM. Our single-cell RNA sequencing data indicates that neuronal groups innervating MM all express the mechanically gated PIEZO-2 channel but at considerably different levels. We hypothesize that neurons innervating the MM have distinct neuron type- dependent responses to mechanical stimuli, and TMDM-driven plasticity. Whole-cell patch-clamp electrophysiology will be used to investigate mechano-gated current properties in different TG neuronal groups innervating MM in naïve and TMDM mice at the initiation of pain. Finally, using in vivo imaging, regulation of different mechanical modalities by TMDM condition will be assessed. The results from this proposal will have a positive impact by outlining novel therapeutic strategies and candidate targets for the prevention and treatment of debilitating masticatory myalgia.

项目摘要/摘要影响咀嚼肌肉（TMDM）的颞下颌疾病是最普遍的群体慢性口面疼痛状况。由咬肌（MM）引起的TMDM慢性疼痛很常见。我的长期目标是阐明控制TMDM慢性发展的基本机制并了解MM支配神经元的功能和TMDM诱导的可塑性。我最近证明小鼠和私人的MM主要由具有独特的髓鞘A纤维支配电生理特征和受体组成。进一步揭示这些神经元的身份我们进行了单细胞RNA测序，并确定了神经支配MM的独特类型的神经元类型。选择性标记可用于特定操纵这些神经元簇的活动。主该提案的目的是定义MM神经TG神经元基团在进度中的贡献 TMDM慢性。该提议的中心假设是支配MM的神经元已专门神经元类型依赖于TMDM慢性发展和经历的不同贡献 TMDM期间机械门控响应的独特可塑性。为了检验这一假设，我们新开发将雇用小鼠慢性按摩肌疼痛（肌痛）的临床相关模型。 AIM 1将定义通过测量，不同类型的神经元在TMDM开发中支配MM的贡献使用鬼脸得分，冯·弗雷，有条件的地方回避和咬伤力的机械性超敏反应。做这，我们将利用转基因小鼠线的可用性和我们的单细胞数据来操纵神经元特定组的TG神经元支配MM的活性。设计器受体专门激活设计师药物（Dreadd）将用于抑制神经元活动。 AIM 2将检查TMDM的影响在神经支配MM的神经元组的机械门控反应上。我们的单细胞RNA测序数据表明神经支配MM的神经元组均表达机械门控的压电-2通道，但在相当不同的水平。我们假设神经支配MM的神经元具有独特的神经元类型 - 对机械刺激和TMDM驱动的可塑性的依赖性响应。全细胞斑块钳电生理学将用于研究不同TG神经元组的机械门控电流特性在疼痛的启发下，在幼稚和TMDM小鼠中支配MM。最后，使用体内成像，调节将评估通过TMDM条件的不同机械方式。该提议的结果将有一个通过概述新的治疗策略和预防和治疗的候选目标，积极影响使乳房肌痛的衰弱。