TRP Channels and Air Pollution

TRP 通道和空气污染

• 批准号: 8372197
• 负责人: Christopher A Reilly
• 金额: $ 33.64万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-17 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8372197
• 关键词: Acute; Address; Adverse effects; Affect; Afferent Neurons; Agonist; Air; Air Pollution; Apoptotic; Arbitration; Attenuated; Benzene; Biological Assay; Caring; Cell Surface Receptors; Cells; Chemicals; Chronic; Chronic Disease; Clinical Treatment; Coal; Collection; Complex; Cytochrome P450; Data; Development; Diesel Exhaust; Epithelial Cells; Event; Functional disorder; Genes; Goals; Health; Homeostasis; Human; Image; Individual; Inflammatory; Interleukin-6; Interleukin-8; Interleukins; Intervention; Investigation; Ion Channel; Ion Channel Protein; Knockout Mice; Link; Literature; Lung; Lung Compliance; Mechanics; Mediating; Mediator of activation protein; Medical; Metalloproteases; Modeling; Molecular; Molecular Target; Morbidity - disease rate; Mus; NAD(P)H dehydrogenase (quinone) 1, human; NADP; NQO1 gene; Neurokinin A; Neurons; Particulate; Pathology; Pathway interactions; Persons; Physiological; Population; Proteins; Public Health; Receptor Inhibition; Research; Research Project Grants; Respiratory physiology; Risk; Shapes; Site; Smoke; Somatostatin; Structure of parenchyma of lung; Substance P; Substance P Receptor; Surface; TRP channel; TRPA1 Channel; TRPV1 gene; Techniques; Testing; Tissues; Toxic effect; Tumor Necrosis Factor-alpha; Variant; Wood material; adverse outcome; base; cDNA Arrays; chemical release; clinically relevant; effective therapy; environmental particulate; fascinate; fly ash; functional group; gene induction; improved; innovation; lung injury; mutant; particle; particle exposure; particulate pollutant; population based; preprotachykinin A; prevent; programs; protein expression; receptor; respiratory; response; sensor; therapeutic development; therapeutic target

DESCRIPTION (provided by applicant): The long-term goal of our research is to improve care of persons adversely affected by particulate components of air pollution (PM) by elucidating specific molecular pathways that mediate adverse respiratory responses to PM. The immediate goals of this project are to establish the molecular and chemical basis for differential activation of the recently discovered "PM-sensing" Ca++ channels, TRPA1, V1, and M8, using two representative combustion-derived particles (cdPM): diesel PM (DEP) and coal fly ash (CFA1), to reveal the contributions of these ion channels in determining PM-induced changes in airway cell homeostasis and respiratory function. Our hypothesis is: TRPA1, V1, and M8 are differentially activated by cdPM as a function of its physical/chemical composition, receptor-specific chemo- and mechano-sensing domains, and cellular expression/localization of TRPA1, V1, and M8 channels. Furthermore, activation of TRPA1, V1 and/or M8 by cdPM are pivotal events underlying the pneumotoxic effects of DEP, CFA1, and similar environmental cdPM. Our specific aims are: 1) pinpoint the regions of TRPA1, V1, and M8 required for activation by DEP and CFA1; 2) link TRPA1, V1, and/or M8 activation with specific airway cellular responses to DEP and CFA1; and 3) demonstrate TRPA1, V1, and/or M8 as mediators of pathophysiological responses of lung tissue to DEP and CFA1. The hypothesis and aims of this study are based on fascinating results showing that several PM, including DEP and CFA1, interact with these specific ion channel proteins at the surface of lung cells, and through unique pharmacological mechanisms, regulate discrete cellular and lung responses that underlie commonly observed PM-induced pulmonary morbidities. Our supporting data demonstrate TRPA1 is predominantly, but not exclusively, activated by reactive chemicals released from DEP and another environmentally relevant cdPM; wood smoke PM (WSP), while TRPV1, M8, and to a lesser extent A1, are uniquely activated by mechanical perturbation of cell surface receptor domains by insoluble components of DEP, CFA1, and other model PM. Neuronal stimulation and subsequent reduction in lung compliance elicited by DEP are inhibited by the TRPA1 antagonist HC-030031, and both neurons and bronchial epithelial cells are stimulated by CFA1 via TRPV1, with pro-inflammatory and pro-apoptotic gene induction in lung epithelial cells and lung tissue being largely dependent upon TRPV1 expression and function (i.e., inhibited by the antagonist LJO-328 or in TRPV1-/- mice). Upon completion of the proposed studies, we will provide conclusive evidence that TRPA1, V1, and M8 are specific molecular pathways that link air pollution to commonly observed adverse outcomes in respiratory tissue. This information is essential for both identifying highly sensitive individuals at greatest risk for developing health problems due to air pollution and developing innovative clinical treatments to protect such people from the adverse effects of PM. PUBLIC HEALTH RELEVANCE: Our objective is to elucidate the basis by which environmental particulate pollutants (PM) adversely affect humans such that tests can be developed to identify individuals at greatest risk of PM-induced toxicities and specific and effective medical interventions can be developed to selectively attenuate the adverse effects of PM on human respiratory (and possibly other) health issues. This project will investigate two fundamental questions central to achieving these objectives and to overcoming limitations in our ability to prevent the adverse effects of polluted air in both acute and chronic exposure scenarios. The questions are: 1) what proteins, and molecular features of these proteins, detect different types of PM? and 2) does activation of a specific ion channel by a specific type of PM regulate lung injury, respiratory dysfunction, or even chronic disease? Answers to these questions are critical to understanding the broad health effects linked to environmental PM exposure by population-based studies and for the development of new and effective ways to selectively mitigate the adverse effects of heterogeneous environmental PM in humans.

描述（由申请人提供）：我们研究的长期目标是通过阐明介导对 PM 的不良呼吸反应的特定分子途径，改善对受到空气污染 (PM) 颗粒成分不利影响的人员的护理。该项目的直接目标是建立差异激活的分子和化学基础 最近发现的“PM 传感”Ca++ 通道 TRPA1、V1 和 M8，使用两种代表性的燃烧衍生颗粒 (cdPM)：柴油 PM (DEP) 和煤飞灰 (CFA1)，揭示这些离子的贡献确定 PM 引起的气道细胞稳态和呼吸功能变化的通道。我们的假设是：TRPA1、V1 和 M8 被 cdPM 不同程度地激活，与其物理/化学成分、受体特异性化学和机械传感域以及 TRPA1、V1 和 M8 通道的细胞表达/定位有关。此外，cdPM 对 TRPA1、V1 和/或 M8 的激活是 DEP、CFA1 和类似环境 cdPM 的肺毒性作用的关键事件。我们的具体目标是：1）查明 DEP 和 CFA1 激活所需的 TRPA1、V1 和 M8 区域； 2) 将 TRPA1、V1 和/或 M8 激活与对 DEP 和 CFA1 的特定气道细胞反应联系起来； 3)证明TRPA1、V1和/或M8是肺组织对DEP和CFA1病理生理反应的介体。这项研究的假设和目的基于令人着迷的结果，这些结果表明，包括 DEP 和 CFA1 在内的多种 PM 与肺细胞表面的这些特定离子通道蛋白相互作用，并通过独特的药理学机制，调节潜在的离散细胞和肺部反应。常见的 PM 诱发的肺部疾病。我们的支持数据表明，TRPA1 主要但并非完全由 DEP 和另一种与环境相关的 cdPM 释放的反应性化学物质激活；木烟 PM (WSP)，而 TRPV1、M8 和较小程度的 A1，则通过 DEP、CFA1 和其他模型 PM 的不溶性成分对细胞表面受体域的机械扰动而独特地激活。 TRPA1 拮抗剂 HC-030031 抑制 DEP 引起的神经元刺激和随后的肺顺应性降低，CFA1 通过 TRPV1 刺激神经元和支气管上皮细胞，并在肺上皮细胞中诱导促炎和促凋亡基因，肺组织很大程度上依赖于 TRPV1 表达和功能（即被拮抗剂 LJO-328 或在 TRPV1-/- 小鼠中抑制）。完成拟议的研究后，我们将提供确凿的证据，证明 TRPA1、V1 和 M8 是将空气污染与呼吸组织中常见不良后果联系起来的特定分子途径。这些信息对于识别因空气污染而面临健康问题风险最大的高度敏感个体以及开发创新的临床治疗方法以保护这些人免受颗粒物的不利影响至关重要。 公共健康相关性：我们的目标是阐明环境颗粒污染物 (PM) 对人类产生不利影响的基础，以便开发测试来识别最有可能遭受 PM 引起的毒性风险的个体，并制定具体有效的医疗干预措施来选择性地减轻 PM 对人类呼吸系统（以及可能的其他）健康问题的不利影响。该项目将研究两个基本问题，这些问题对于实现这些目标以及克服我们在急性和慢性暴露情况下防止污染空气的不利影响的能力的限制至关重要。问题是：1) 哪些蛋白质以及这些蛋白质的分子特征可以检测不同类型的 PM？ 2) 特定类型的 PM 激活特定离子通道是否可以调节肺损伤、呼吸功能障碍甚至慢性疾病？这些问题的答案对于通过基于人群的研究了解与环境 PM 暴露相关的广泛健康影响以及开发新的有效方法来选择性减轻异质环境 PM 对人类的不利影响至关重要。