The role of TRPM8 and artemin in migraine

TRPM8 和 artemin 在偏头痛中的作用

基本信息

批准号：
10222801
负责人：
David D McKemy
金额：
$ 20.63万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10222801
关键词：
Ablation Absence of pain sensation Address Affect Antibodies Behavioral Blood Vessels Cell Degranulation Cell Line Complex Disease Family Foundations Funding Mechanisms Future GDNF receptors Genetic Hand Human Hyperalgesia Inflammation Mediators Investigation Knowledge Laboratories Lead Ligands Link Literature Maintenance Mediating Mediator of activation protein Menthol Migraine Modeling Molecular Mus Mutation Neurons Nitric Oxide Nitric Oxide Synthase Nitroglycerin Nociception Pain Pathogenesis Pathologic Pathology Pathway interactions Peripheral Phenotype Population Production Receptor Cell Regulation Rodent Model Role Sensory Signal Pathway Signal Transduction Susceptibility Gene Testing Therapeutic Transgenic Organisms Untranslated RNA Work allodynia behavior test cell growth regulation experience experimental study genome-wide glial cell-line derived neurotrophic factor inducible gene expression mast cell mouse model neurotrophic factor pain behavior receptor response therapeutic target tool

项目摘要

Migraine is one of the most debilitating disorders in humans, affecting greater than 15% of the population with minimal therapeutic avenues for migraine sufferers. The challenge in treatment is that migraine involves many sensory pathways, including irregular excitability in central and peripheral nociceptive neurons. To address this complex disorder, several groups have recently performed genome-wide associated studies (GWAS) to ascertain candidate molecules mediating migraine pathology, identifying the cold and menthol receptor TRPM8 as a migraine susceptibility gene. Interestingly, these studies identified mutations only in noncoding regions of TRPM8, therefore making it likely that these mutations alter expression levels and not channel function. While it is not known what role, if any, the channel has in migraine, TRPM8 serves an important role in pathological cold pain, suggesting there may be a corollary between cold and migraine pain. Recently, we found that the glial cell line-derived neurotrophic factor (GDNF) family ligand artemin and its receptor, GDNF family receptor alpha 3 (GFRa3), are the principle mediators of TRPM8-dependent cold pain, of note as each has also been linked to migraine. These results have led us to the hypothesis that TRPM8 channels and afferents, via altered signaling due to artemin interacting with GFRa3, are a component of the underlying mechanisms of migraine. To test this, we propose to use this exploratory mechanism to (1) determine if TRPM8 channels or neurons are involved in migraine-like pain behaviors in mice, then (2) similarly ask if artemin and GFRa3 are required for migraine pathogenesis. At the completion of this exploratory study, we will have determined if either TRPM8 or artemin/GFRa3 signaling serve a role in migraine. Moreover, the proposed experiments will determine if either of the signaling pathways under consideration are relevant for migraine, potentially serving as the foundation for future investigations.

偏头痛是使人类最衰弱的疾病之一，影响超过 15% 的人口偏头痛患者的治疗途径最少。治疗中的挑战是偏头痛涉及许多感觉通路，包括中枢和外周伤害感受的不规则兴奋性神经元。为了解决这种复杂的疾病，几个小组最近进行了全基因组研究相关研究（GWAS）以确定介导偏头痛病理学的候选分子，确定寒冷和薄荷醇受体TRPM8作为偏头痛易感基因。有趣的是，这些研究发现仅在TRPM8的非编码区域发生突变，因此这些突变很可能改变表达水平而不是通道功能。虽然尚不清楚该渠道在其中扮演什么角色（如果有的话）偏头痛中，TRPM8 在病理性冷痛中发挥着重要作用，这表明可能有一个推论介于寒冷和偏头痛之间。最近，我们发现胶质细胞源性神经营养因子 (GDNF) 家族配体 artemin 及其受体 GDNF 家族受体 α 3 (GFRa3) 是其原理值得注意的是，TRPM8 依赖性冷痛介质也与偏头痛有关。这些结果使我们得出这样的假设：TRPM8 通道和传入神经通过 artemin 导致的信号改变与 GFRa3 相互作用，是偏头痛潜在机制的一个组成部分。为了测试这一点，我们建议使用这种探索性机制来（1）确定 TRPM8 通道或神经元是否参与小鼠的偏头痛样疼痛行为，然后 (2) 同样询问偏头痛是否需要 artemin 和 GFRa3 发病。完成这项探索性研究后，我们将确定 TRPM8 或 artemin/GFRa3 信号在偏头痛中发挥作用。此外，拟议的实验将确定是否正在考虑的任何一个信号通路都与偏头痛相关，有可能作为为今后的调查奠定基础。