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引起的偏头痛症状的血管周机制 项目摘要 偏头痛是一种使神经肽基因相关肽的神经系统衰弱的神经系统疾病 （CGRP）。它影响了15％的人口，是残疾年龄的第二多年原因。 确实，超过40％的妇女在一生中会经历偏头痛。令人兴奋的发展是 FDA最近批准了一类新的CGRP靶向药物，旨在预防偏头痛。但是，这是一个批判 仍然需要，因为这些药物对所有患者都不适用。提高基于CGRP的药物的功效 并为新药物开发铺平了道路，我们需要更多地了解CGRP在偏头痛中的工作方式。这 该项目的目的是确定CGRP在外围和中央站点的作用机制 引发类似偏头痛的症状。科学的前提是偏头痛涉及对 CGRP，由表明CGRP的临床研究支持的CGRP既需要且足以引起 偏头痛。在过去的资金期间，我们开发了对CGRP作用敏感的转基因小鼠。 CGRP敏感的小鼠的表达升高，称为人的CGRP受体的亚基 受体活性调节蛋白1（HRAMP1）。我们发现CGRP会导致偏头痛样症状 （恐惧症）通过中枢神经系统（CNS）和周围的不同但可能重叠的作用。 在这里，我们建议使用光使用野生型和HRAMP1转基因小鼠中的偏头痛症状 厌恶作为恐惧症的指标，触摸灵敏度和鬼脸作为疼痛的指标。我们 假设CGRP在硬脑膜和丘脑的血管周部作用，引起类似偏头痛的症状 恐惧症和疼痛。具体而言，我们建议CGRP诱导的外围的血管舒张改变了 三角血管微环境，并从集中促进CGRP作为神经调节剂的作用 后丘脑区域。第一个目标将测试外围CGRP机制是否涉及对 硬脑膜中的血液和淋巴管和常驻肥大细胞。第二个目标将测试中央是否 CGRP机制涉及后丘脑后核中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两个目的。这些研究将提供 深入了解使CGRP能够通过脉管系统中心和外围行动的机制 影响神经系统疾病的感觉功能。尽管我们对偏头痛的理解取得了进步 过去的十年，许多问题仍未得到答复，部分原因是适当的动物模型缺乏。这 使用我们的新颖CGRP敏感的HRAMP1小鼠是一种挑战的创新方法 目前关于CGRP在外围和大脑中血管作用的教条。该提议的结果 将是诱导偏头痛症状的硬脑膜和中枢神经系统中血管周围CGRP作用的发现。 重要的是，这将有助于开发针对偏头痛的血管靶向和中枢神经系统侵蚀剂治疗剂。