TRP Channels and Air Pollution

TRP 通道和空气污染

基本信息

批准号：
8663692
负责人：
Christopher A Reilly
金额：
$ 33.19万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
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/8663692
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

项目摘要

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.

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来改善受空气污染颗粒成分（PM）的不利影响的人。该项目的直接目标是建立差分激活的分子和化学基础使用两个代表性燃烧衍生的颗粒（CDPM）：柴油PM（DEP）和煤粉灰分（CFA1），在最近发现的“ PMSMESING” CA ++通道（TRPA1，V1和M8）中，以揭示这些离子的贡献确定PM诱导的气道细胞稳态变化和呼吸功能的通道。我们的假设是：TRPA1，V1和M8被CDPM差异激活，这是其物理/化学组成，受体特异性化学感应结构域以及TRPA1，V1和M8通道的细胞表达/定位的函数。此外，通过CDPM激活TRPA1，V1和/或M8是DEP，CFA1和类似环境CDPM的肺毒性作用的关键事件。我们的具体目的是：1）查明由DEP和CFA1激活所需的TRPA1，V1和M8的区域； 2）链接TRPA1，V1和/或M8激活与对DEP和CFA1的特定气道细胞反应； 3）展示TRPA1，V1和/或M8作为肺组织对DEP和CFA1的病理生理反应的介体。这项研究的假设和目的是基于令人着迷的结果，表明包括DEP和CFA1在内的几个PM与肺部细胞表面的这些特定离子通道蛋白相互作用，并通过独特的药理机制来调节离散的细胞和肺反应，这些反应是基础的。通常观察到PM诱导的肺病。我们的支持数据表明，TRPA1主要是由DEP释放的反应性化学物质和另一个与环境相关的CDPM激活的，但不是仅限于此。木烟PM（WSP），而TRPV1，M8和较小程度的A1是通过DEP，CFA1和其他模型PM的不溶性组件的机械扰动来唯一激活细胞表面受体域的。 TRPA1拮抗剂HC-030031抑制神经元刺激和随后的DEP引起的肺合顺顺作，以及神经元和支气管上皮细胞均通过TRPV1刺激了CFA1，并被促炎和促脑诱导细胞和促脑诱导细胞中的Lung上皮细胞中的cfa1刺激肺组织在很大程度上取决于TRPV1的表达和功能（即受拮抗剂LJO-328或TRPV1 - / - 小鼠的抑制）。拟议的研究完成后，我们将提供结论性的证据，表明TRPA1，V1和M8是特定的分子途径，它们将空气污染与通常观察到的呼吸道组织不良后果联系起来。该信息对于确定由于空气污染而出现健康问题的高度敏感人士以及开发创新的临床治疗以保护这些人免受PM的不良影响而产生健康问题的风险至关重要。