Determining the functions of tooth-innervating neurons in dental sensation

确定牙齿神经支配神经元在牙齿感觉中的功能

• 批准号: 10535494
• 负责人: Joshua James Emrick
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10535494
• 关键词: Address; Adult; Afferent Neurons; Assessment tool; Behavior; Behavior Control; Biological Assay; Calibration; Categories; Dedications; Dental; Dental Pulp; Dentists; Dentition; Dependence; Development; Diameter; Disease; Epidemic; Esthesia; Exposure to; Face; Functional Imaging; Goals; Health; Inflammation; Injury; Ion Channel; Knowledge; Label; Link; Machine Learning; Mechanics; Medical; Mentors; Modeling; Molar tooth; Molecular; Monitor; Mus; Neurons; Nociception; Nociceptors; Opioid Analgesics; Orofacial Pain; Osmosis; Pain; Pain management; Perception; Peripheral; Phase; Physiological; Population; Prevalence; Quality of life; Reporter; Research; Role; Scientist; Sensory; Signal Transduction; Stimulus; Structure; Structure of trigeminal ganglion; Surveys; System; Testing; Tooth structure; Toothache; Touch sensation; Training; Trigeminal System; Work; addiction; behavioral response; calcium indicator; career development; clinical pain; effective therapy; feature detection; imaging platform; in vivo; in vivo calcium imaging; intense pain; mortality; mouse model; nerve supply; non-opioid analgesic; novel strategies; novel therapeutics; optogenetics; orofacial; pain relief; prescription opioid; prevent; response; sensory input; sensory mechanism; sensory stimulus; somatosensory; transcriptomic profiling; transcriptomics

PROJECT SUMMARY/ABSTRACT Pain has a major impact on the quality of life, remains difficult to alleviate, and has contributed to the over- prescription of opioid analgesics that is often linked to the recent epidemic of addiction and mortality. Clinical pain results from inappropriate signaling from the somatosensory system, caused by changes in activity of peripheral sensory neurons and/or central processing of this input. Molar teeth are richly innervated by specialized somatosensory neurons, yet we only notice tooth sensation when injury or inflammation trigger intense toothache. This transformation of innocuous dental sensation to exquisite pain underlies the most common form of orofacial pain. Here I will address the roles, responses, and molecular mechanisms of sensory neurons innervating teeth in health and inflammation in order to expose both tooth-specific and common pain mechanisms, and spur new ideas for development and testing of non-opioid analgesics to alleviate pain. The overall objective of this application is to determine the cellular and molecular mechanisms responsible for tooth sensation (mentored phase) and address how sensory input from the teeth may be transformed to drive pain (independent phase). Powerful, cutting-edge approaches will be leveraged to develop a new and comprehensive view of the physiological roles of tooth-innervating trigeminal sensory neurons. To achieve this goal, Dr. Joshua Emrick will work with a mentoring team including Dr. Nicholas Ryba (primary mentor), Dr. Mark Hoon (co-mentor), and Drs. Alexander Chesler and Jennifer L. Gibbs (collaborators). In Aim 1, Dr. Emrick will explore the function of the tooth-innervating neurons by studying their central connectivity and manipulating them with optogenetics. To this end, standard nocifensive assays as well as orofacial feature categorization using machine learning will be used to evaluate pain responses. In Aim 2, Dr. Emrick will determine how trigeminal neurons respond to stimulation of teeth using an in vivo calcium imaging platform. In combination, these studies will reveal new information about tooth sensation, provide a tractable model for understanding pain, and a strategy for developing targeted clinical pain therapies. Importantly, the proposed training will support Dr. Emrick’s career development in his transition into independence as a dentist-scientist.

项目概要/摘要 疼痛对生活质量有重大影响，仍然难以缓解，并导致过度治疗。 阿片类镇痛药的处方通常与最近流行的成瘾和死亡有关。 临床疼痛是由体感系统发出不适当的信号引起的，而体感系统的信号变化是由体感系统的变化引起的。 外周感觉神经元的活动和/或该输入的中央处理。 臼齿受到专门的体感神经元的丰富支配，但我们只注意到牙齿的感觉 当受伤或炎症引发剧烈牙痛时，这种无害的牙齿感觉的转变。 剧烈的疼痛是最常见的口面部疼痛的原因，在这里我将阐述以下角色： 感觉神经元在健康和炎症中的反应和分子机制 为了揭示牙齿特有的和常见的疼痛机制，并激发新的发展思路 以及测试非阿片类镇痛药以减轻疼痛。 该应用的总体目标是确定负责的细胞和分子机制 用于牙齿感觉（指导阶段）并解决牙齿的感觉输入如何转换 驱除疼痛（独立阶段）。 并全面了解牙齿支配的三叉神经感觉神经元的生理作用。 为了实现这一目标，Joshua Emrick 博士将与包括 Nicholas Ryba 博士（小学 导师）、Mark Hoon 博士（共同导师）、Alexander Chesler 博士和 Jennifer L. Gibbs 博士（合作者）。 目标 1，Emrick 博士将通过研究牙齿神经元的中枢神经元来探索其功能 连接性并通过光遗传学操纵它们为此目的，标准伤害分析以及。 在目标 2 中，将使用机器学习进行口面部特征分类来评估疼痛反应。 Emrick 博士将使用体内钙确定三叉神经元如何响应牙齿刺激 成像平台。 结合起来，这些研究将揭示有关牙齿感觉的新信息，提供易于处理的模型 理解疼痛，以及开发有针对性的临床疼痛疗法的策略。 拟议的培训将支持埃姆里克博士作为一名独立人士过渡到独立的职业发展 牙医科学家。