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.

偏头痛是人类中最令人衰弱的疾病之一，影响了人口的15％以上偏头痛患者的治疗途径最少。治疗的挑战是偏头痛涉及许多感觉途径，包括中央和周围伤害性的不规则兴奋性神经元。为了解决这一复杂疾病，几个小组最近进行了全基因组相关研究（GWAS）确定介导偏头痛病理学的候选分子，确定冷和薄荷醇受体TRPM8作为偏头痛易感基因。有趣的是，这些研究确定了仅在TRPM8的非编码区域中突变，因此这些突变可能会改变表达水平而不是通道函数。虽然尚不知道该渠道在偏头痛，TRPM8在病理冷痛中起重要作用，表明可能有必不可少的在寒冷和偏头痛之间。最近，我们发现神经胶质细胞系衍生的神经营养因子（GDNF）家族配体Artemin及其受体GDNF家族受体Alpha 3（GFRA3）是原理 trpm8依赖性冷痛的介体，因为每种疼痛也与偏头痛有关。这些结果导致我们通过Artemin引起的信号改变了TRPM8通道和传入的假设与GFRA3相互作用是偏头痛基本机制的组成部分。为了测试这一点，我们建议使用此探索机制来（1）确定TRPM8通道或神经元是否参与小鼠中的偏头痛疼痛行为，然后（2）同样询问偏头痛是否需要阿耳梅明和gfra3 发病。这项探索性研究完成时，我们将确定TRPM8还是 Artemin/gfra3信号传导在偏头痛中发挥作用。此外，提出的实验将确定是否所考虑的任何一个信号通路都与偏头痛有关，有可能用作未来调查的基础。