Perivascular mechanisms of CGRP-induced migraine symptoms

降钙素基因相关肽引起偏头痛症状的血管周围机制 项目摘要 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)。它影响了15%的人口，是导致多年来残疾的第二大原因。 事实上，超过40%的女性会在一生中经历偏头痛。一个令人兴奋的发展是 最近FDA批准了一类新的CGRP靶向药物，旨在预防偏头痛。然而，一个关键的 需求依然存在，因为这些药物并不是对所有患者都有效。提高降钙素基因相关肽类药物的疗效 并为新药开发铺平道路，我们需要更多地了解CGRP在偏头痛中的作用。这个 该项目的目标是确定CGRP在外围和中央部位的作用机制 引发类似偏头痛的症状。科学的前提是偏头痛涉及对 降钙素基因相关肽，得到了临床研究的支持，研究表明降钙素基因相关肽既是必需的，也是足以引起 偏头痛。在过去的资助期间，我们开发了对CGRP作用敏感的转基因小鼠。 CGRP致敏的小鼠CGRP受体的一个亚单位人类的表达增加 受体活性修饰蛋白1(HRAMP1)。我们发现降钙素基因相关肽会引起偏头痛样症状 (恐光症)由中枢神经系统(CNS)和外周的不同但可能重叠的行为所致。 在这里，我们建议使用LIGH来测量野生型和hRAMP1转基因小鼠的偏头痛样症状 厌恶是恐光的指标，触摸敏感和做鬼脸是疼痛的指标。我们 假设降钙素基因相关肽作用于硬脑膜和丘脑的血管周围部位，引起偏头痛样症状 畏光和疼痛。具体地说，我们认为降钙素基因相关肽诱导的外周血管扩张改变了 三叉神经血管微环境，在中枢促进降钙素基因相关肽作为神经调节剂的作用。 丘脑后部区域。第一个目标是测试外周CGRP机制是否涉及 硬脑膜中的血管和淋巴管以及常驻肥大细胞。第二个目标将测试中央银行是否 降钙素基因相关肽的机制涉及丘脑后核团的血管周围和神经调节作用。 在这两个目标中将使用互补的遗传和药理学策略。这些研究将提供 深入了解CGRP通过血管系统在中枢和外周发挥作用的机制 在神经疾病中影响感觉功能。尽管我们对偏头痛的理解在过去几年中取得了进展 在过去的十年里，许多问题仍然没有答案，部分原因是缺乏合适的动物模型。这个 使用我们的新型CGRP致敏的hRAMP1小鼠代表了一种创新的方法来挑战 目前关于降钙素基因相关肽在外周和大脑中的血管作用的教条。这项提议的结果是 将是硬脑膜和中枢神经系统中血管周围CGRP活动的发现，这些活动会导致偏头痛样症状。 重要的是，这将促进偏头痛血管靶向和中枢神经系统渗透疗法的发展。

Perivascular mechanisms of CGRP-induced migraine symptoms Project Summary Migraine is a debilitating neurological condition involving the neuropeptide calcitonin gene-related peptide (CGRP). It affects 15% of the population and is the second leading cause of years lived with a disability. Indeed, over 40% of women will experience migraine during their lifetime. An exciting development is the recent FDA approval of a new class of CGRP-targeted drugs designed to prevent migraine. However, a critical need remains because these drugs do not work for all patients. To improve the efficacy of CGRP-based drugs and pave the way for new drug development, we need to know more about how CGRP works in migraine. The objective of this project is to identify the mechanisms by which CGRP acts at both peripheral and central sites to trigger migraine-like symptoms. The scientific premise is that migraine involves increased sensitivity to CGRP, which is supported by clinical studies that have shown CGRP is both required and sufficient to cause migraine. During the past funding period, we developed transgenic mice that are sensitized to CGRP actions. The CGRP-sensitized mice have elevated expression of a subunit of the CGRP receptor called human receptor activity-modifying protein 1 (hRAMP1). We found that CGRP causes a migraine-like symptom (photophobia) by distinct, but possibly overlapping actions in the central nervous system (CNS) and periphery. Here we propose to measure migraine-like symptoms in wildtype and hRAMP1 transgenic mice, using light aversion as an indicator of photophobia, and touch sensitivity and grimace as indicators of pain. We hypothesize that CGRP acts at perivascular sites in the dura and thalamus to cause migraine-like symptoms of photophobia and pain. Specifically, we propose that CGRP-induced vasodilation in the periphery alters the trigeminovascular microenvironment, and that centrally it facilitates the action of CGRP as a neuromodulator in the posterior thalamic region. The first aim will test whether peripheral CGRP mechanisms involve actions on blood and lymphatic vessels and resident mast cells in the dura. The second aim will test whether central CGRP mechanisms involve perivascular and neuromodulatory actions in the posterior thalamic nuclei. Complementary genetic and pharmacological strategies will be used in both aims. These studies will provide insight into the mechanisms that enable CGRP to act both centrally and peripherally, via the vasculature, to affect sensory functions in a neurological disorder. 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. The use of our novel CGRP-sensitized hRAMP1 mice represents an innovative approach for challenging the current dogma regarding the vascular roles of CGRP in the periphery and brain. The outcome of this proposal will be the uncovering of perivascular CGRP actions in the dura and CNS that induce migraine-like symptoms. Importantly, this will facilitate development of vascular-targeted and CNS-penetrant therapeutics for migraine.