Determining the functions of tooth-innervating neurons in dental sensation

项目摘要/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 阿片类镇痛剂的处方，这往往与最近的成瘾和死亡率流行有关。 临床疼痛是由躯体感觉系统发出的不适当信号引起的，这是由于 外周感觉神经元的活动和/或该输入的中央处理。 磨牙由专门的体感神经元丰富地神经支配，但我们只注意到牙齿的感觉 当受伤或发炎引发剧烈牙痛时。这种无害的牙齿感觉的转变 剧烈的疼痛是最常见的口腔面部疼痛的基础。在这里，我将讲述这些角色， 健康和炎症状态下牙齿感觉神经元的反应和分子机制 以揭示牙齿特有的和常见的疼痛机制，并刺激新的发展思路 以及测试非阿片类止痛药以减轻疼痛。 这个应用的总体目标是确定细胞和分子机制 用于牙齿感觉(指导阶段)，并说明牙齿的感觉输入如何转换 驱使疼痛(独立期)。将利用强大的尖端方法开发一种新的 以及对支配牙齿的三叉神经感觉神经元的生理作用的全面综述。至 为了实现这一目标，Joshua Emrick博士将与包括Nicholas Ryba博士(主要)在内的指导团队合作 Mentor)、Mark Hoon博士(共同导师)、Alexander Chesler博士和Jennifer L.Gibbs博士(合作者)。在……里面 目标1，Emrick博士将通过研究牙齿神经细胞的中枢来探索其功能 连通性，并用光遗传学操纵它们。为此，标准的明示分析以及 使用机器学习的面部特征分类将用于评估疼痛反应。在目标2中， 埃姆里克博士将确定三叉神经细胞对使用体内钙刺激牙齿的反应 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，提供一个易于处理的模型 了解疼痛，以及开发有针对性的临床疼痛疗法的战略。重要的是， 拟议的培训将支持Emrick博士的职业发展，使他过渡到独立的 牙医兼科学家。

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.