Role of TRP Channels in Environmental Irritant-Induced Headache

TRP 通道在环境刺激引起的头痛中的作用

• 批准号: 8246435
• 负责人: JOYCE H HURLEY
• 金额: $ 32.59万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8246435
• 关键词: 4 hydroxynonenal; Ablation; Acrolein; Address; Afferent Neurons; Agonist; Air; Air Pollution; Binding; Biochemical; Biochemistry; Blood Vessels; Blood flow; Breathing; Calcitonin Gene-Related Peptide; Calcium; Calcium Signaling; Capsaicin; Cerebrum; Chemical Structure; Chemicals; Complex; Covalent Interaction; Data; Diagnostic; Dilatation - action; Disease; Dominant-Negative Mutation; Dura Mater; Economic Burden; Electrophysiology (science); Environmental Health; Environmental Irritants; Etiology; Exhibits; Exposure to; Family; Formaldehyde; Gases; Gated Ion Channel; Genes; Genetic; Goals; Head; Headache; Headache Disorders; Health; Health Benefit; Incidence; Indoor Air Pollution; Inflammation; Injury; Ion Channel; Irritants; Knockout Mice; Knowledge; Laser-Doppler Flowmetry; Ligands; Link; Measurement; Measures; Mediating; Meningeal; Meninges; Methods; Migraine; Molecular; Molecular Target; Multiple Chemical Sensitivity; Nasal cavity; Neurons; Nose; Oral cavity; Oxidative Stress; Pain; Patients; Plants; Pollution; Public Health; Rattus; Receptor Activation; Regulation; Relative (related person); Research; Rodent Model; Role; Sick Building Syndrome; Signal Transduction; Small Interfering RNA; Stimulus; Structure of trigeminal ganglion; Substance P; Symptoms; Synapses; System; TRPV1 gene; Testing; Tissues; Trigeminal System; Trigeminal nerve structure; Up-Regulation; Vasodilation; Vasodilator Agents; base; capsaicin receptor; cigarette smoking; desensitization; environmental agent; exhaust; fluorescence imaging; member; mustard oil; neurotransmitter release; novel; overexpression; pollutant; public health relevance; receptor; research study; response; small hairpin RNA

DESCRIPTION (provided by applicant): Headache is one of the most frequent complaints attributed to environmental air pollution (indoor and outdoor), but the total impact on public health is difficult to quantify. Increased exposure to chemical irritants in the air we breathe may be responsible for the increased incidence of migraine as well as more recently described disorders such as Sick building syndrome (SBS) and Multiple chemical sensitivity (MCS). The most common complaint in patients suffering SBS or MCS is headache and both disorders have been linked to exposure to chemical irritants. In recent years, a new molecular target for diverse chemical structures, including several components of environmental irritants, has emerged. It has been demonstrated that a member of the transient receptor potential (TRP) superfamily of ligand-gated ion channels, TRPA1, is activated by a novel mechanism involving covalent interaction between many chemicals and the receptor-channel leading to excitation of sensory neurons expressing TRPA1 and elevations in intracellular calcium. In this proposal, we will examine a specific hypothesis linking inhaled chemical irritants to the induction of headache symptoms. We propose that chemical activation of TRPA1 homomers, or TRPA1/TRPV1 heteromers on trigeminal neurons innervating the meninges results in release of calcitonin gene-related peptide (CGRP), a potent vasodilator implicated in migraine. The resultant vasodilatation provokes headache symptoms. To examine this hypothesis, we address three specific aims using a combination of approaches in a rodent model: (1) Examination of whether TRPA1 in trigeminal neurons innervating the dura is involved in stimulating meningeal blood flow by nasally administered chemical irritants. (2) Determination of the role of CGRP release in the dura in mediating increased meningeal blood flow induced by chemical irritants. (3) Determination of the relative roles of TRPA1 and TRPV1 in mediating chemical irritant induced responses in trigeminal neurons and of meningeal blood flow. Our experiments will combine Laser Doppler flowmetry, measurements of CGRP release, fluorescence imaging of intracellular calcium, cellular electrophysiology, biochemistry, gene knock-out mice for TRPA1 or TRPV1, and pharmacological and molecular interference to address these issues. Understanding how headache is provoked by chemical irritants is an important question in environmental health with the potential for a significant impact on public health. PUBLIC HEALTH RELEVANCE: Pollution related health issues are becoming more prevalent and creating a significant societal and economic burden. Headache is the most common symptom associated with indoor and outdoor air pollution but how environmental irritants, such as formaldehyde and acrolein, cause headache is not known. Sick Building Syndrome and Multiple Chemical Sensitivity, disorders associated with environmental irritants may have similar mechanistic bases as migraine, a common headache disorder. The pain associated with migraine is thought to be due to activation of the trigeminal sensory neurons which synapse on the cerebral blood vessels, the trigeminovascular system. The goal of the proposed studies is to determine whether environmental irritants activate the trigeminovascular system via binding to chemical sensing receptors known as TRP channels.

描述（由申请人提供）：头痛是归因于环境空气污染（室内和室外）最常见的投诉之一，但对公共卫生的总影响很难量化。我们呼吸的空气中对化学刺激物的暴露增加可能是偏头痛的发生率增加以及最近描述的疾病，例如病态建筑综合征（SBS）和多种化学敏感性（MCS）。患有SBS或MCS的患者最常见的抱怨是头痛，这两种疾病都与化学刺激性的暴露有关。近年来，已经出现了一种新的分子靶标，包括多种化学结构，包括环境刺激物的几个组成部分。已经证明，配体门控离子通道的瞬时受体电位（TRP）超家族TRPA1被激活，该机制涉及许多化学物质与受体通道之间的共价相互作用，从而激发了表达TRPA1的感觉神经元的激发，表达TRPA1的感觉和内部钙化含量。在此提案中，我们将研究一个特定的假设，将吸入化学刺激物与诱导头痛症状联系起来。我们提出，TRPA1同源物的化学激活或TRPA1/TRPV1杂体在三叉神经元上支配的脑膜神经元会导致降钙素基因相关肽（CGRP）的释放，这是一种有效的血管舒张剂，与偏头痛有关。由此产生的血管扩张会引起头痛症状。为了审查这一假设，我们使用啮齿动物模型中的方法组合解决了三个特定目的：（1）研究杜拉的三叉神经元中的TRPA1是否参与了通过鼻施用的化学刺激物刺激脑膜血流。 （2）确定CGRP释放在硬脑膜中的作用在介导化学刺激物引起的脑膜血流增加中的作用。 （3）测定TRPA1和TRPV1在三叉神经元和脑膜血流中介导化学刺激性诱导反应中的相对作用。我们的实验将结合激光多普勒流量，测量CGRP释放的测量，细胞内钙的荧光成像，细胞电生理学，生物化学，TRPA1或TRPV1的基因敲除小鼠以及药理和药理和分子分子干扰以解决这些问题。了解化学刺激物如何引起头痛是环境健康的一个重要问题，其可能会对公共卫生产生重大影响。 公共卫生相关性：与污染有关的健康问题越来越普遍，并造成了巨大的社会和经济负担。头痛是与室内和室外空气污染相关的最常见症状，但是环境刺激物（例如甲醛和丙烯醛）如何导致头痛。病态建筑综合征和多种化学敏感性，与环境刺激物相关的疾病可能具有与常见头痛障碍偏头痛相似的机械基础。与偏头痛相关的疼痛被认为是由于三叉神经元的激活，这些神经元在大脑血管上突触，即三角血管系统。该研究的目的是确定环境刺激物是否通过与称为TRP通道的化学传感受体结合来激活三角血管系统。