Defining the generators of spontaneous trigeminal pain

定义自发性三叉神经痛的产生因素

• 批准号: 10217834
• 负责人: David Avrahm Yarmolinsky
• 金额: $ 10.18万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10217834
• 关键词: Advisory Committees; Afferent Neurons; Animals; Area; Award; Behavioral; Behavioral Paradigm; Brain Stem; Calcium; Consultations; Cranial Nerves; Craniofacial Pain; Face; Facial Pain; Functional disorder; Generations; Genetic; Genetic Transcription; Goals; Image; Imaging Techniques; Injury; Leadership; Link; Measurement; Mentors; Modeling; Monitor; Mus; Neuronal Injury; Neurons; Neuropathy; Output; Pain; Pain Measurement; Pathologic; Patients; Peripheral; Phase; Physiological; Population; Postdoctoral Fellow; Research; Sensory; Stimulus; Supervision; Synaptic Transmission; Techniques; Therapeutic Intervention; Training; Trigeminal Pain; Trigeminal System; Trigeminal nerve structure; Work; activating transcription factor 3; awake; design; dorsal horn; experience; experimental study; in vivo calcium imaging; nerve injury; novel; pain behavior; pain sensation; painful neuropathy; programs; responsible research conduct; skills; spontaneous pain; synaptic inhibition; targeted treatment

Project Summary/Abstract Patients suffering from facial neuropathic pain commonly experience sensations of pain in the absence of any relevant environmental stimulus. The identity of the neurons responsible for generating this spontaneous pain remains unresolved, creating a barrier to rational targeting of treatment. The scientific goal of this proposal is to establish the neuronal substrates responsible for initiating stimulus-independent neuropathic pain. In previous post-doctoral work, the candidate has developed an in vivo calcium imaging technique to monitor activity in large populations of genetically defined trigeminal neurons in mice, and in AIM 1 will apply this approach to define the transcriptional identity and injury status of primary sensory neurons giving rise to spontaneous activity in a model of trigeminal nerve injury. Genetic access to the injury status of sensory neurons has been achieved through generation of a novel mouse line expressing CreERT2 from the Atf3 locus, directing expression specifically to injured neurons. AIM 2 will explicitly investigate the causal link between ectopic activity in specific sensory populations and manifestations of spontaneous pain. Output from defined sensory populations will be silenced through genetically directed inhibition of synaptic transmission, and the resulting effect on behavioral and physiological surrogates of stimulus-independent pain sensation will be assessed. These experiments will rely on extensive training in pain-related behavioral paradigms by the primary mentor, with assistance from the BCH Pain Core. The results of AIMs 1 & 2 will identify peripheral generators of spontaneous neuropathic pain. AIM 3 will examine nerve injury-induced spontaneous activity in the medullary dorsal horn, the first central area processing craniofacial pain information, and dissect the functional relationship between central spontaneous activity and specific peripheral inputs. This will rely on novel techniques to perform calcium imaging in the brainstem of awake behaving animals, which will be developed in close consultation with Dr. Mark Andermann. The mentored phase of this award will be supervised by an advisory committee of Drs. Clifford Woolf, Mark Andermann, David Ginty and Stephen Liberles. An integrated training plan provides intensive training in the modeling and measurement of neuropathic pain, design and analysis of assays for pain behavior, scientific leadership skills, and responsible conduct of research, thus providing a platform for successful transition to direction of an independent research program investigating mechanisms of normal and pathological pain.

项目总结/摘要 患有面部神经性疼痛的患者通常在没有任何疼痛感的情况下经历疼痛感。 相关的环境刺激。负责产生这种自发性疼痛的神经元的身份 仍然没有得到解决，这对合理确定治疗目标造成了障碍。这项提案的科学目标是 建立负责引发刺激非依赖性神经性疼痛的神经元底物。前几 在博士后工作中，该候选人开发了一种体内钙成像技术，以监测大范围内的活动， 群体的遗传定义的三叉神经元在小鼠中，并在AIM 1将应用这种方法来定义 在模型中引起自发活动的初级感觉神经元的转录特性和损伤状态 三叉神经损伤通过遗传学方法可以获得感觉神经元的损伤状态， 从Atf 3基因座产生表达CreERT 2的新小鼠系，特异性地指导表达 受伤的神经元目的2将明确调查之间的因果关系异位活动在特定的感觉 自发性疼痛的人群和表现。来自定义的感觉群体的输出将被沉默 通过遗传定向抑制突触传递，以及对行为和 将评估刺激非依赖性痛觉的生理替代物。这些实验将依赖于 在BCH的协助下，由主要导师进行疼痛相关行为范例的广泛培训 疼痛核心AIM 1和2的结果将识别自发性神经性疼痛的外周发生器。AIM 3 将检查神经损伤引起的延髓背角的自发活动， 加工颅面疼痛信息，并解剖中枢自发性疼痛与颅面疼痛的功能关系。 活动和特定的外围输入。这将依赖于新的技术来进行钙成像， 清醒行为动物的脑干，这将在与马克·安德曼博士密切磋商后开发。 该奖项的指导阶段将由Clifford Woolf博士，Mark 安德曼，大卫金蒂和斯蒂芬利伯莱斯。综合培训计划提供以下方面的强化培训： 神经病理性疼痛的建模和测量，疼痛行为测定的设计和分析，科学 领导技能和负责任的研究行为，从而为成功过渡到 一个独立的研究项目的方向，调查正常和病理性疼痛的机制。