Determining the functions of tooth-innervating neurons in dental sensation

项目总结/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- 阿片类镇痛药处方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的不适当信号传导引起的， 外周感觉神经元的活动和/或该输入的中枢处理。 臼齿是由专门的躯体感觉神经元丰富的支配，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 是最常见的口面部疼痛的基础在这里，我将讨论角色， 反应，以及健康和炎症中支配牙齿的感觉神经元的分子机制。 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来缓解疼痛。 本申请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），并解决如何将来自牙齿的感觉输入转换为 独立阶段（Independent Phase）将利用强大的尖端方法开发新的 和牙齿支配三叉神经感觉神经元的生理作用的全面看法。到 为了实现这一目标，约书亚埃姆里克博士将与一个指导小组，包括博士尼古拉斯Ryba（小学） 导师）、Mark Hoon博士（共同导师）、亚历山大切斯勒博士和Jennifer L.吉布斯（合作者）。在 目的1，Emrick博士将通过研究牙齿神经元的中枢神经系统来探索牙齿神经元的功能。 连接并通过光遗传学操纵它们。为此，标准的伤害反应测定以及 使用机器学习的口面特征分类将用于评估疼痛反应。在目标2中， 博士埃姆里克将利用体内钙离子通道来确定三叉神经元对牙齿刺激的反应 成像平台。 结合起来，这些研究将揭示关于牙齿感觉的新信息，提供一个易于处理的模型， 了解疼痛，并制定有针对性的临床疼痛治疗策略。重要的是 拟议的培训将支持埃姆里克博士的职业发展，在他过渡到独立作为一个 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.