Perivascular mechanisms of CGRP-induced migraine symptoms

CGRP 诱发偏头痛症状的血管周围机制

• 批准号: 10596016
• 负责人: Andrew F Russo
• 金额: $ 6.9万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10596016
• 关键词: Affect; Animal Model; Behavior; Biological; Blocking Antibodies; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain region; Calcitonin Gene-Related Peptide; Calcitonin-Gene Related Peptide Receptor; Clinical; Clinical Research; Closure by clamp; Complex; Data; Development; Drug Design; Drug Targeting; Dura Mater; Endothelial Cells; Fiber; Funding; Genetic; Goals; Headache; Human; Injections; Knowledge; Light; Lymphocyte; Measures; Migraine; Modeling; Mus; Neuraxis; Neurogenic Inflammation; Neurologic; Neuromodulator; Neuropeptides; New Agents; Outcome; Outcome Study; Pain; Patients; Peptide Signal Sequences; Pericytes; Peripheral; Persons; Pharmaceutical Preparations; Pharmacology; Phenotype; Photophobia; Play; Population; Posterior Thalamic Nuclei; Public Health; Research; Retina; Role; Sensory; Sensory Disorders; Signal Transduction; Site; Smooth Muscle; Smooth Muscle Myocytes; Societies; Symptoms; Systemic blood pressure; Tactile; Testing; Thalamic structure; Therapeutic; Tissues; Touch sensation; Transgenic Mice; Vasodilation; Woman; Work; allodynia; base; cell type; central sensitization; chronic painful condition; clinically relevant; disability; drug development; experience; experimental study; improved; innovation; insight; lymphatic vessel; mast cell; mouse model; nervous system disorder; neuroregulation; new therapeutic target; novel; novel drug class; novel therapeutics; optogenetics; overexpression; pain signal; parabrachial nucleus; peptide drug; prevent; receptor; receptor-activity-modifying protein; therapeutic target; vascular contributions

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.

CGRP诱导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，是导致残疾的第二大原因。 事实上，超过40%的女性在一生中会经历偏头痛。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 因为这些药物并非对所有患者都有效。提高CGRP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。的 本研究的目的是确定CGRP在外周和中枢的作用机制 引发类似偏头痛的症状科学的前提是偏头痛涉及对 CGRP，这是支持的临床研究表明，CGRP是必要的，并足以导致 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致敏小鼠的CGRP受体亚单位表达升高，称为人CGRP受体亚单位。 受体活性修饰蛋白1（hRAMP1）。我们发现降钙素基因相关肽会导致偏头痛样症状 （恐惧症）通过在中枢神经系统（CNS）和外周的不同但可能重叠的作用。 在这里，我们建议测量偏头痛样症状的野生型和hRAMP 1转基因小鼠，使用光 厌恶作为恐惧症的指标，触摸敏感性和鬼脸作为疼痛的指标。我们 假设CGRP作用于硬脑膜和丘脑中的血管周围部位，引起偏头痛样症状， 恐惧症和疼痛。具体地说，我们认为CGRP诱导的外周血管舒张改变了 三叉神经血管微环境，并在中枢促进CGRP作为神经调质的作用， 丘脑后部第一个目标是测试外周CGRP机制是否涉及对 血管和淋巴管以及硬脑膜中的常驻肥大细胞。第二个目标将测试中央政府是否 CGRP机制涉及丘脑后核的血管周围和神经调节作用。 互补的遗传和药理学策略将用于这两个目标。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， 影响神经系统疾病的感觉功能。尽管我们对偏头痛的理解在过去几年中取得了进展， 在过去的十年中，许多问题仍然没有答案，部分原因是缺乏适当的动物模型。的 使用我们的新型CGRP致敏的hRAMP1小鼠代表了一种挑战 目前关于CGRP在外周和脑中的血管作用的教条。这一提议的结果 将揭示血管周围CGRP在硬脑膜和中枢神经系统中的作用，从而诱导偏头痛样症状。 重要的是，这将促进血管靶向和CNS渗透剂治疗偏头痛的发展。