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Determining the functions of molecularly defined populations of nociceptors in spinal and dental pain

确定分子定义的伤害感受器群体在脊柱和牙齿疼痛中的功能

基本信息

批准号：
9980200
负责人：
Ishmail John Abdus-Saboor
金额：
$ 29.07万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9980200
关键词：
Ablation Acute Affect Afferent Neurons Americas Animal Behavior Basic Science Behavior Bioethics Calcium Cations Consultations Coupled Data Dental Pulp Dental Schools Diphtheria Toxin Electrophysiology (science)Ensure Esthesia Family Foundations G-Protein-Coupled Receptors Generations Grant Head Health Hypersensitivity Hypersensitivity skin testing Image Inflammatory Injury Ion Channel Knowledge Laboratories Learning Skill Light Measures Mechanics Mediating Mentors Methods Mission Modeling Modernization Molar tooth Molecular Molecular Biology Molecular Genetics Mus National Institute of Dental and Craniofacial Research Neurites Neurons Neuropeptides Neurosciences Nociception Nociceptors Oral health Orofacial Pain Pain Pain Nature Pain Threshold Pathologic Patients Persistent pain Phase Physiological Play Population Postdoctoral Fellow Principal Investigator Pruritus Public Health Publishing Reporting Research Research Personnel Role Running School Dentistry Spinal Spinal Cord Spine pain Stimulus Structure of trigeminal ganglion Synaptic Transmission System TRP channel TRPV1 gene Techniques Technology Testing Thermal Hyperalgesias Tooth structure Toothache Training Writing base chronic pain common symptom design experimental study improved in vivo insight loss of function member molecular marker mouse genetics neural circuit novel optogenetics orofacial pain sensation population based post-doctoral training receptor recombinase-mediated cassette exchange response sensory stimulus side effect skills spinal nerve posterior root spontaneous pain targeted treatment therapeutic target

项目摘要

Project Summary/Abstract Chronic pain of the body and orofacial region represents a major health burden and the neural circuit mechanisms underlying long-lasting pain remain largely unknown. The current treatment options for pain are largely non-specific, have unwanted side effects, poor efficacy in many patients, and some have abuse potential. Therefore, the need to design more targeted therapies is imperative and to accomplish this, knowledge of the neural circuits responsible for pain is critical. The long-term objectives of this research are to define neural circuit mechanisms responsible for chronic pain, particularly in the orofacial region. The principal investigator has made use of a new mouse line in which he can target blue-light sensitive ion channels to molecular populations of nociceptors and optogenetically activate them in vivo. His preliminary data shows that he can trigger long-lasting spontaneous pain with this novel and non-invasive technique. He has also shown that he can use similar technologies with the Cre-lox system to ablate molecularly defined populations of nociceptors to investigate their functions in pain. In Aim 1 of the K99 mentored phase he will use optogenetics coupled with animal behavior and electrophysiology to uncover neural circuit mechanisms important for the transition from acute to chronic pain. In Aim 2 of the K99 mentored phase he will use a tooth pulp injury model with an apparatus to measure orofacial pain coupled with ablation or activation of a molecularly defined population of nociceptors to determine their functions in dental pain. Lastly, during the R00 independent phase in Aim 3, the principal investigator will use the the same tooth pulp injury model together with the skills and techniques acquired during the mentored phase to investigate two additional populations of nociceptors that may be involved in sensitivity to thermal stimuli following dental pulp injury. Completion of the three listed aims will make him proficient in using mouse molecular genetics to control the activity of nociceptors while investigating their functions in dental pain. The principal investigator will learn the skills and new techniques necessary to accomplish the proposed research under the guidance of his mentoring team (Drs. Brian Schmidt, Wenqin Luo, Minghong Ma, Michael Nusbaum, and Jonathan Raper) and his consultants (Drs. Elliot Hersh, and Syngcuk Kim, and Yuanxiang Tao), who have pioneering expertise in using the listed methods and models. Importantly, his mentoring committee collectively has a very strong track record of training postdoctoral fellows in transitioning into independent investigators. He will also engage in seminars and take coursework on modern neuroscience techniques, grant writing, bioethics training, and training on running a laboratory. Combining the new skills learned during the K99 mentored phase with his prior expertise in molecular biology and mouse genetic targeting, will ensure a strong technical foundation to launch an independent laboratory dissecting neural circuit mechanisms responsible for orofacial system pain, which are still very poorly defined.

项目总结/摘要身体和口面部区域的慢性疼痛是一个主要的健康负担，长期疼痛的潜在机制在很大程度上仍然未知。目前疼痛的治疗方案是大部分是非特异性的，有不必要的副作用，在许多患者中疗效差，有些人滥用潜力因此，需要设计更多的靶向治疗是势在必行的，为了实现这一目标，了解引起疼痛的神经回路至关重要。这项研究的长期目标是定义负责慢性疼痛的神经回路机制，特别是在口面部区域。校长研究人员利用一种新的小鼠品系，他可以靶向蓝光敏感的离子通道，伤害感受器的分子群体并在体内光遗传学地激活它们。他的初步数据显示，他可以用这种新颖的非侵入性技术引发持久的自发性疼痛。他还表示，他可以使用类似的技术与Cre-lox系统消融分子定义的人口，研究它们在疼痛中的功能。在K99指导阶段的目标1中，他将使用光遗传学结合动物行为学和电生理学来揭示神经回路机制，从急性疼痛到慢性疼痛。在K99指导阶段的目标2中，他将使用牙髓损伤模型使用测量口面疼痛的装置，群体的伤害感受器，以确定其在牙痛中的功能。最后，在R 00独立阶段在目标3中，主要研究者将使用相同的牙髓损伤模型，在指导阶段获得的技术，以研究另外两个伤害感受器群体，可能与牙髓损伤后对热刺激的敏感性有关。完成所列三个目标这将使他精通使用小鼠分子遗传学来控制伤害感受器的活动，研究它们在牙痛中的作用首席研究员将学习技能和新技术在他的指导小组的指导下完成拟议的研究所必需的（布莱恩博士施密特、Wenqin Luo、Minghong Ma、Michael Nusbaum和Jonathan Raper）及其顾问（Elliot博士 Hersh、Syngcuk Kim和Yuanxiang Tao），他们在使用所列方法方面具有开创性的专业知识，模型重要的是，他的指导委员会集体拥有非常强大的培训记录博士后研究员转变为独立调查员。他还将参加研讨会，现代神经科学技术课程，赠款写作，生物伦理学培训，以及运行实验室将K99指导阶段学到的新技能与他之前的专业知识相结合，分子生物学和小鼠遗传靶向，将确保强大的技术基础，推出一个独立的实验室解剖神经回路机制负责口面系统疼痛，这是仍然定义不清。