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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.

项目概要/摘要影响咀嚼肌的颞下颌疾病 (TMDM) 是最常见的一组疾病慢性口面部疼痛。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 慢性发展的根本机制并了解支配 MM 的神经元的功能和 TMDM 诱导的可塑性。我最近证明小鼠和灵长类动物的 MM 主要由有髓鞘 A 纤维支配，具有独特的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，并确定了支配 MM 的独特神经元类型。选择标记可用于对这些神经元簇的活动进行特定操作。主要该提案的目的是确定 MM 支配 TG 神经元群在进展中的贡献 TMDM 慢性化。该提议的中心假设是，支配 MM 的神经元具有专门化的功能。神经元类型依赖性对 TMDM 慢性发展的独特贡献并经历 TMDM 期间机械门控反应的独特可塑性。为了检验这个假设，我们新开发的将采用小鼠慢性咬肌疼痛（肌痛）的临床相关模型。目标 1 将定义通过测量不同类型的神经元支配 MM 在 TMDM 发展中的贡献使用鬼脸评分、von Frey、条件性位置回避和咬合力来评估机械过敏。要做的事为此，我们将利用转基因小鼠品系的可用性和我们的单细胞数据来操纵神经元支配 MM 的特定 TG 神经元组的活动。设计受体独家激活设计药物（DREADD）将用于抑制神经元活动。目标 2 将检验 TMDM 的影响关于支配 MM 的神经元群的机械门控反应。我们的单细胞 RNA 测序数据表明支配 MM 的神经元群都表达机械门控 PIEZO-2 通道，但在水平相差很大。我们假设支配 MM 的神经元具有不同的神经元类型 - 对机械刺激的依赖性反应和 TMDM 驱动的可塑性。全细胞膜片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初始疼痛和 TMDM 小鼠中，在疼痛开始时神经支配 MM。最后，利用体内成像，调节将评估 TMDM 条件下的不同机械模式。该提案的结果将概述新的治疗策略和预防和治疗的候选目标，产生积极影响使人衰弱的咀嚼肌痛。