CGRP's effect on hearing and balance in a mouse model of migraine

CGRP 对偏头痛小鼠模型听力和平衡的影响

• 批准号: 10174909
• 负责人: ANNE E LUEBKE
• 金额: $ 32.7万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10174909
• 关键词: Affect; Agonist; Auditory system; Blocking Antibodies; Calcitonin Gene-Related Peptide; Calcitonin-Gene Related Peptide Receptor; Cannulas; Cerebrospinal Fluid; Chronic; Clinic; Clinical; Clinical Trials; Cochlear Nerve; Control Groups; Development; Dizziness; Equilibrium; Exhibits; Female; Fiber; Future; Goals; Headache; Hearing; Homologous Gene; Hypersensitivity; Impairment; Implant; Infusion procedures; Injections; Intraperitoneal Injections; Labyrinth; Light; Measures; Migraine; Motion Sickness; Mus; Nausea; Neurons; Neuropeptides; Patients; Performance; Peripheral; Pharmaceutical Preparations; Phonophobias; Photophobia; Photosensitivity; Population; Posture; Pre-Clinical Model; Predisposition; RAMP1; Recovery; Recurrence; Route; Saline; Sensory; Serotonin; Signal Transduction; Symptoms; Testing; Therapeutic; Transgenic Mice; Ventricular; Vertigo; Wild Type Mouse; base; effective therapy; experience; intraperitoneal; mouse model; nervous system disorder; nestin protein; novel therapeutics; otoconia; peptide I; receptor; response; sound; translational study; triptans; vestibulo-ocular reflex

Migraine is a severe and chronic neurological disorder that affects ~18% of people worldwide, majority female (3:1). Migraine is characterized by recurrent attacks of debilitating headaches and nausea, with heightened sensory sensitivities, such as light (photophobia) and sound (phonophobia). Recently it has become recognized that ~42% of migraine patients also suffer from balance problems and dizziness, termed vestibular migraine (VM). VM is a major cause of vertigo in dizziness clinics, and is estimated to affect 1% of the overall population. Clinically, triptans (serotonin 5-HT 1B/1D receptor agonists) can reduce photophobia and headaches in migraine, but often do not relieve other VM symptoms. Thus, there is an urgent need for validated preclinical models for VM. The neuropeptide calcitonin gene-related peptide (CGRP) is recognized as a key player in migraine based on the efficacy of CGRP blockers in clinical trials against headache, and injection of CGRP triggers migraine. We have developed CGRP-sensitized transgenic mouse models for migraine that have heightened responses to light (photophobia) when CGRP is delivered either centrally or systemically. We have shown that CGRP blockers can block CGRP-induced photosensitivity in these mice, yet CGRP blockers delivered systemically cannot effectively penetrate the CNS, and these blockers are not effective against centrally-induced photophobia, suggesting that photosensitivity in migraine involves both systemic and central components. CGRP is also widely distributed throughout the vestibular CNS, and CGRP-containing efferent fibers project to all inner ear endorgans. CGRP is also signaling in the vestibular and auditory systems, as we discovered in a different mouse model, that the loss of CGRP reduces the vestibulo-ocular reflex (VOR) gain, reduces otolith- evoked dynamics reduces, reduces sound-evoked activity in the cochlear nerve, and impairs rotarod (balance) performance. Yet, it is not yet known if CGRP is acting centrally or peripherally in VM; which would influence treatment routes and efficacy. We propose to measure mouse homologues of clinical VM symptoms namely; phonophobia, imbalance, nausea, and motion-sickness susceptibility; and will investigate these measures in three mouse lines: i) wildtype (WT) littermate controls and CGRP-sensitized mouse models with ii) neuronally- sensitized CGRP receptors (nestinRAMP1) or iii) globally-sensitized CGRP receptors (global RAMP1). Our hypothesis is that elevated CGRP-sensitivity will contribute to increased sensitivities found in VM; and that these VM symptoms will be ameliorated by CGRP blockers. Information gained from these studies will provide a direct assessment of whether CGRP-sensitized mouse models that have been shown to mirror the photophobia of migraine, can also mirror deficits observed in VM. Such a preclinical model of VM could be used for future translational studies to develop and test new therapeutics. !

偏头痛是一种严重而慢性的神经系统疾病，影响了全球约18％的人，多数 女（3：1）。偏头痛的特征是衰弱的头痛和恶心的反复发作， 增强的感觉敏感性，例如光（恐惧症）和声音（Phonophobia）。最近有 认识到约有42％的偏头痛患者也患有平衡问题和头晕，称为 前庭偏头痛（VM）。 VM是头晕诊所眩晕的主要原因，估计会影响1％ 总体人口。临床上，triptans（5-羟色胺5-HT 1B/1D受体激动剂）可以减少恐惧症 和偏头痛的头痛，但通常无法缓解其他VM症状。因此，迫切需要 VM验证的临床前模型。 神经肽基因基因相关肽（CGRP）被认为是基于偏头痛的关键参与者 关于CGRP阻滞剂在针对头痛的临床试验中的功效，并注射CGRP触发偏头痛。 我们为偏头痛开发了CGRP敏感的转基因小鼠模型 当CGRP从中央或系统地传递时，请亮（恐惧症）。我们已经证明了CGRP 阻滞剂可以阻止这些小鼠的CGRP诱导的光敏性，但CGRP阻滞剂已系统地传递 无法有效地穿透中枢神经系统，这些阻滞剂对中心诱导的 恐惧症，表明偏头痛中的光敏性涉及全身和中央组成部分。 CGRP也广泛分布在整个前庭中心，含CGRP的传出纤维项目 所有内耳的内脏。 CGRP也在前庭和听觉系统中发出信号，正如我们在 不同的小鼠模型，CGRP的丧失会减少前庭反射（VOR）增益，从而减少了耳石 - 诱发的动态减少，减少人工耳蜗中的声音诱发活性，并损害rotarod（平衡） 表现。然而，尚不清楚CGRP在VM中的集中或外围表现。会影响 治疗路线和功效。我们建议测量临床VM症状的小鼠同源物，即； 语音恐惧症，失衡，恶心和动感易感性；并将调查这些措施 三种小鼠线：i）野生型（wt）窝窝对照和cgrp敏化的小鼠模型，具有ii）神经元 - 敏化的CGRP受体（Nestinramp1）或iii）全球敏感的CGRP受体（全局RAMP1）。我们的 假设是，CGRP敏感性升高将导致VM中发现的敏感性提高。和 这些VM症状将被CGRP阻滞剂改善。 从这些研究中获得的信息将直接评估CGRP敏感的小鼠 已显示出可以反映偏头痛的恐惧症的模型也可以反映在VM中观察到的缺陷。 这种VM的临床前模型可用于未来的翻译研究来开发和测试新的 疗法。呢