CGRP-Induced Light Aversion in a Preclinical Migraine Model

描述（由申请人提供）：偏头痛是一种衰弱的神经系统疾病，涉及神经肽降钙素基因相关肽（CGRP）。该项目的总体目标是确定CGRP触发偏头痛常见症状畏光的机制。畏光症是对通常不令人疼痛的光线的痛苦反应。这些研究的一个有用工具是nestin/hRAMP1转基因小鼠，它对CGRP的作用敏感。小鼠的神经系统中CGRP受体亚基的表达升高，称为人类受体活性修饰蛋白1 （hRAMP1）。Nestin/hRAMP1小鼠对至少两种感官刺激的反应增强：触觉和光线。光厌恶表型类似于畏光症，并通过CGRP的中央管理大大增强。在化学诱导的肥大细胞脱颗粒和轻度应激模式下，小鼠也表现出增强的光厌恶行为。压力是偏头痛最常见的诱因之一，也会诱发硬脑膜肥大细胞脱颗粒。有证据表明，偏头痛是一种神经紊乱，可因炎症信号而加剧：硬脑膜肥大细胞激活三叉神经伤害性通路，肥大细胞脱颗粒引发偏头痛样头痛，抗炎药物通常用于偏头痛。我们假设CGRP可以在丘脑中起作用，引发应激性神经源性炎症后的光厌恶。这一假设是基于最近的一项发现，即后丘脑神经元对硬脑膜和光刺激都很敏感。此外，CGRP可以激活硬脑膜肥大细胞、三叉神经和丘脑后神经元。因此，存在一个cgrp依赖的应激诱导肥大细胞激活途径，使丘脑神经元对光敏感，导致畏光。第一个目标是确定肥大细胞在光厌恶行为中的作用。将比较nestin/hRAMP1和对照小鼠对化学激活剂和轻度应激范式的光厌恶反应。第二个目的是确定后丘脑是否是CGRP和肥大细胞诱导的光厌恶的中枢神经系统靶点。将采用互补的药理学和遗传学策略。这些目标将为压力在动物模型中引发偏头痛样症状的机制提供见解。显然，除了CGRP外，偏头痛还涉及许多基因。因此，基于hramp1的策略提供了一种利用已定义小鼠系统的优势来研究复杂疾病的创新方法。拟议研究的意义在于它们的转化潜力，偏头痛的患病率强调了这一点，几乎每5名女性中就有1名受到影响。尽管在过去十年中我们对偏头痛的理解有所进步，但许多问题仍未得到解答，部分原因是缺乏适当的动物模型。为了解决这些问题，我们组建了一个具有CGRP、偏头痛、疼痛药理学和小鼠行为方面专业知识的跨学科团队。该建议的影响将是一个有效的临床前模型，用于开发偏头痛的新疗法的转化研究。

DESCRIPTION (provided by applicant): Migraine is a debilitating neurological condition involving the neuropeptide calcitonin gene-related peptide (CGRP). The overall objective of this project is to identify mechanisms by which CGRP triggers photophobia, a common symptom of migraine. Photophobia is a painful response to ordinarily non-painful levels of light. A useful tool for these studies is the nestin/hRAMP1 transgenic mouse, which is sensitized to CGRP actions. The mice have elevated nervous system expression of a subunit of the CGRP receptor called human receptor activity-modifying protein 1 (hRAMP1). Nestin/hRAMP1 mice have heightened responses to at least two sensory stimuli: touch and light. The light aversive phenotype is analogous to photophobia and is greatly enhanced by central administration of CGRP. The mice also display enhanced light aversive behavior following chemically induced mast cell degranulation and a mild stress paradigm. Stress is one of the most common triggers of migraine and also induces dural mast cell degranulation. There is evidence that migraine is a neural disorder that can be exacerbated by inflammatory signals: dural mast cells activate trigeminal nociceptive pathways, mast cell degranulation triggers migraine-like headaches, and anti-inflammatory drugs are commonly used for migraine. We hypothesize that CGRP can act in the thalamus to trigger light aversion following stress-induced neurogenic inflammation. This hypothesis is based on a recent finding that posterior thalamic neurons are sensitive to both dural and light stimulation. Furthermore, CGRP can activate dural mast cells, trigeminal neurons, and posterior thalamic neurons. Thus, there is a CGRP-dependent pathway for stress-induced mast cell activation to sensitize thalamic neurons to light, leading to photophobia. The first aim will establish the contribution of mast cells in light aversive behavior. Light aversion in response to a chemical activator and a mild stress paradigm will be compared between nestin/hRAMP1 and control mice. The second aim will identify whether the posterior thalamus is a CNS target of CGRP- and mast cell-induced light aversion. Complementary pharmacological and genetic strategies will be used. These aims will provide insight to the mechanisms by which stress can trigger a migraine-like symptom in an animal model. Clearly, a host of genes will be involved in migraine in addition to CGRP. Hence, the hRAMP1-based strategy provides an innovative approach using the advantages of a defined mouse system for the study of complex diseases. The significance of the proposed studies is their translational potential, which is underscored by the prevalence of migraine, affecting almost 1 in every 5 women. Despite advances in our understanding of migraine over the past decade, many questions remain unanswered, in part due to the paucity of appropriate animal models. To address these issues, we have assembled an interdisciplinary team with expertise in CGRP, migraine, pain pharmacology, and mouse behavior. The impact of this proposal will be a validated preclinical model for translational studies to develop new therapeutics for migraine.