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）：头痛是环境空气污染（室内和室外）引起的最常见的投诉之一，但对公共健康的总体影响很难量化。我们呼吸的空气中化学刺激物的暴露增加可能是导致偏头痛以及最近描述的疾病（例如病态建筑综合症（SBS）和多种化学敏感性（MCS））发病率增加的原因。患有 SBS 或 MCS 的患者最常见的主诉是头痛，这两种疾病都与接触化学刺激物有关。近年来，出现了针对多种化学结构（包括环境刺激物的多种成分）的新分子靶标。已经证明，配体门控离子通道瞬时受体电位 (TRP) 超家族的成员 TRPA1 是通过一种新机制激活的，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，从而导致表达 TRPA1 的感觉神经元的兴奋以及细胞内钙的升高。在这项提案中，我们将研究一个将吸入化学刺激物与诱发头痛症状联系起来的具体假设。我们提出，对支配脑膜的三叉神经元上的 TRPA1 同聚物或 TRPA1/TRPV1 异聚物进行化学激活，会导致降钙素基因相关肽 (CGRP) 的释放，降钙素基因相关肽 (CGRP) 是一种与偏头痛有关的强效血管舒张剂。由此产生的血管舒张会引起头痛症状。为了检验这一假设，我们在啮齿动物模型中结合使用多种方法来解决三个具体目标：（1）检查支配硬脑膜的三叉神经元中的 TRPA1 是否参与经鼻给予化学刺激物刺激脑膜血流。 (2)确定硬脑膜中CGRP释放在介导化学刺激物引起的脑膜血流量增加中的作用。 (3)确定TRPA1和TRPV1在介导化学刺激诱导的三叉神经元反应和脑膜血流中的相对作用。我们的实验将结合激光多普勒血流测定、CGRP 释放测量、细胞内钙荧光成像、细胞电生理学、生物化学、TRPA1 或 TRPV1 基因敲除小鼠以及药理学和分子干扰来解决这些问题。了解化学刺激物如何引起头痛是环境健康中的一个重要问题，可能对公众健康产生重大影响。 公共卫生相关性：与污染相关的健康问题变得越来越普遍，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，但甲醛和丙烯醛等环境刺激物如何引起头痛尚不清楚。病态建筑综合症和多种化学物质敏感性，与环境刺激物相关的疾病可能与偏头痛（一种常见的头痛疾病）具有相似的机制基础。与偏头痛相关的疼痛被认为是由于三叉神经感觉神经元的激活所致，这些神经元与脑血管（三叉血管系统）上的突触有关。拟议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叉血管系统。