Meningeal Nociceptor-Immune Signaling in Migraine

偏头痛中的脑膜伤害感受器免疫信号传导

基本信息

批准号：
10582390
负责人：
DAN LEVY
金额：
$ 49.17万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10582390
关键词：
Acute Address Affect Afferent Neurons Anatomy Animals Antibodies Anxiety Behavior Biological Response Modifiers Cells Cephalic Chronic Communication Complex Data Development Disease Face Flow Cytometry Foundations Functional disorder Future Goals Headache Image Immune Immune response Immune signaling Immunity Immunoassay Immunohistochemistry Inflammation Mediators Inflammatory Inflammatory Response Leukocytes Lymphocyte Maintenance Mediating Mediator of activation protein Meningeal Meninges Methods Migraine Molecular Monitor Mus Myelogenous Nerve Fibers Neurogenic Inflammation Neuroimmune Neuroimmunomodulation Neuropeptides Neutrophil Infiltration Nociception Nociceptors Pain Pain Measurement Peripheral Play Process Production Proxy Recurrence Role Running Sterility Stimulus T-Lymphocyte T-Lymphocyte Subsets Testing Time Tissues Topical application Vascular Permeabilities Vasodilation allodynia awake base behavior test bone cytokine disability experimental study field study in vivo insight mast cell monocyte nervous system disorder neutrophil novel optogenetics pain behavior prevent recruit response theories therapeutic target trafficking two photon microscopy two-photon vascular factor

项目摘要

Migraine is a multifactorial disorder characterized by recurrent attacks of severe headache and is one of the top causes of global disability. Although migraine has no clear pathophysiological origin, a major theory implicates sterile neurogenic inflammation of the cranial dural meninges as the mechanism that drives persistent meningeal nociception, resulting in the headache during an attack. However, the vascular components of neurogenic inflammation mediated by neuropeptides released from peripheral terminals of activated nociceptors - increased vascular permeability and vasodilation - are now considered neither necessary nor sufficient for migraine headache genesis. This raises the question of whether meningeal neurogenic inflammation is relevant to migraine pain, and if so, could other neurogenically-driven inflammatory processes play a role. A growing body of evidence also points to an immune component in neurogenic inflammation, such that activation of nociceptors promotes immune cell recruitment and regulates their functional responses. Activation of nociceptors, nevertheless, can also suppress inflammatory immune responses. This collaborative project will combine our expertise in meningeal nociception and migraine pain (Levy) and functional interactions between nociceptors and immune cells (Chiu) to explore a non-vascular inflammatory mechanism of migraine involving bidirectional communication between meningeal nociceptors and meningeal immunity that drives migraine headache. We propose novel combinations of powerful methods, including optogenetics, intravital 2-photon microscopy, flow cytometry, multiplex cytokine arrays, and analysis of pain behaviors to study meningeal neuroimmune interactions under conditions that mimic migraine attack onset (acute stimulation) and a severe attack (prolonged stimulation). We will first characterize the meningeal immune response and related migraine-like pain behaviors that develop following selective optogenetic activation of Nav1.8-lineage meningeal nociceptors (Aim 1). Then, based on preliminary data, we will determine the relative contribution of meningeal neutrophils and T cells in mediating these migraine-related pain behaviors (Aim 2). Collectively, these experiments could provide a dramatically better understanding of the role of neurogenic inflammation in migraine pathophysiology and serve as an experimental foundation for future explorations of mechanistic insights into meningeal neuroimmune crosstalk and further testing of specific immune cells and related proinflammatory mediators as potential therapeutic targets for migraine pain.

偏头痛是一种多因素疾病，其特征是反复发作的严重头痛，是最常见的头痛之一全球残疾的原因。尽管偏头痛没有明确的病理生理学起源，但一个主要理论表明颅硬脑膜的无菌性神经源性炎症是驱动持续性脑膜的机制伤害感受，导致发作时头痛。然而，神经源性血管成分由激活的伤害感受器外周末端释放的神经肽介导的炎症 - 增加血管通透性和血管舒张——现在被认为对于偏头痛来说既不是必要的也不是充分的头痛的发生。这就提出了一个问题：脑膜神经源性炎症是否与偏头痛，如果是这样，其他神经源性驱动的炎症过程可能也发挥了作用。成长中的身体大量证据还指出神经源性炎症中的免疫成分，例如伤害感受器的激活促进免疫细胞募集并调节其功能反应。激活伤害感受器，尽管如此，也可以抑制炎症免疫反应。这个合作项目将结合我们的脑膜伤害感受和偏头痛 (Levy) 以及伤害感受器之间功能相互作用的专业知识和免疫细胞（Chiu）探索涉及双向的偏头痛的非血管炎症机制脑膜伤害感受器和脑膜免疫之间的交流导致偏头痛。我们提出强大方法的新颖组合，包括光遗传学、活体 2 光子显微镜、流式细胞术细胞计数、多重细胞因子阵列和疼痛行为分析来研究脑膜神经免疫在模拟偏头痛发作（急性刺激）和严重发作（长时间刺激）的条件下相互作用刺激）。我们将首先描述脑膜免疫反应和相关的偏头痛样疼痛行为 Nav1.8 谱系脑膜伤害感受器选择性光遗传学激活后形成（目标 1）。然后，根据初步数据，我们将确定脑膜中性粒细胞和 T 细胞在调节这些与偏头痛相关的疼痛行为（目标 2）。总的来说，这些实验可以提供更好地了解神经源性炎症在偏头痛病理生理学中的作用并提供服务作为未来探索脑膜神经免疫机制的实验基础潜在的特定免疫细胞和相关促炎介质的串扰和进一步测试偏头痛的治疗目标。