TRP Channels and Air Pollution

TRP 通道和空气污染

• 批准号: 7696333
• 负责人: Christopher A Reilly
• 金额: $ 30.1万
• 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 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7696333
• 关键词: Acetylcysteine; Acute; Agonist; Air; Air Pollutants; Air Pollution; Attenuated; Biological Assay; Biological Markers; Biomedical Research; Breathing; Calcium Channel; Cardiovascular system; Cells; Chemical Agents; Chemicals; Chinese Hamster; Chinese Hamster Ovary Cell; Chronic; Complex; Coupled; Coupling; Data; Disease; Environment; Epithelial; Epithelial Cells; Event; Exposure to; Family; Functional disorder; Future; Ganglia; Genes; Genetic; Health; Heating; Hematoxylin and Eosin Staining Method; Human; In Situ; In Vitro; Individual; Inflammatory; Interleukin-6; Ion Channel; Knockout Mice; Ligands; Link; Lung; Mediating; Mediator of activation protein; Modification; Molecular; Mus; Myxoid cyst; Neutrophilia; Outcome; Ovary; Oxidation-Reduction; Particulate; Particulate Matter; Peroxidases; Persons; Physicians; Pneumonia; Point Mutation; Pollution; Proteins; Receptor Activation; Research; Respiration Disorders; Respiratory distress; Risk; Sampling; Scientist; Site; Site-Directed Mutagenesis; Solid; Solvents; Staining method; Stains; Stimulus; Structure of parenchyma of lung; TRP channel; TRPV1 gene; Testing; Toxic effect; Translating; Variant; Work; chemical property; chemokine; clinically relevant; cytokine; environmental particulate; experience; inhibitor/antagonist; insight; mRNA Expression; metal chelator; mortality; oxidation; prevent; programs; prophylactic; public health relevance; receptor; release of sequestered calcium ion into cytoplasm; respiratory; response; sensor

DESCRIPTION (provided by applicant): Particulate air pollutants (particulate matter; PM) are ubiquitous in the environment. Increases in human respiratory and cardiovascular dysfunction, disease, and mortality have been linked to both short- and long- term exposures to PM. Currently, specific mechanisms of action at the molecular and cellular levels and targeted therapies to reduce the detrimental effects of PM exposures in humans remain undefined. This is, in part, because the gene products that translate the presence of PM into deleterious molecular, cellular and systemic events are essentially unknown. Preliminary data show that TRPV1 and a TRPM8 variant are activated by PM. Furthermore, activation is coupled to increased expression of cytokine/chemokine genes by lung cells in vitro and in the lung. The proposed research will investigate TRPV1, TRPM8, and other TRP family calcium channels as sensors for PM and mediators of toxicity in the lung. The molecular and physico-chemical determinants of TRP channel activation by different PM sub-types will be established using site-directed mutagenesis of TRP channels and physical and chemical modification of PM. TRPV1, TRPM8, and other PM-sensing TRP channels will also be evaluated as mediators of PM toxicity in mice. PM-Induced lung toxicity will be studies using both TRP channel antagonists and TRP channel knockout mice. Furthermore, quantifiable biomarkers that discriminate TRP channel activation in the lung by different PM will be identified and validated. These data will drive future studies of humans who experience respiratory distress during high pollution episodes. The proposed research will establish fundamental mechanisms of PM-induced pulmonary toxicity and provide key insights into mechanisms of PM-induced respiratory distress. Future studies will attempt to link the activation of specific TRP channels with environmentally-induced human respiratory distress. It is anticipated that the combined results of this research will transform future biomedical research investigating the origins of and strategies to treat respiratory disorders and diseases associated with exposure to environmental PM. PUBLIC HEALTH RELEVANCE: This research will identify and characterize proteins in the lung that may potentially determine whether a person develops health problems when they inhale polluted air. Identification of the proteins responsible for sensing and responding to inhaled air pollution as well as the mechanisms by which responses occur will ultimately allow scientists and physicians to establish effective ways to treat and/or prevent sickness due to breathing polluted air.

描述（由申请人提供）： 空气颗粒污染物（颗粒物；PM）在环境中普遍存在。人类呼吸和心血管功能障碍、疾病和死亡率的增加与短期和长期接触颗粒物有关。目前，在分子和细胞水平上的具体作用机制以及减少 PM 暴露对人类有害影响的靶向治疗仍不清楚。部分原因是，将 PM 的存在转化为有害分子、细胞和系统事件的基因产物基本上是未知的。初步数据显示 TRPV1 和 TRPM8 变体被 PM 激活。此外，激活与体外和肺中肺细胞细胞因子/趋化因子基因的表达增加有关。拟议的研究将研究 TRPV1、TRPM8 和其他 TRP 家族钙通道作为 PM 传感器和肺部毒性介质。将利用 TRP 通道的定点诱变和 PM 的物理和化学修饰来建立不同 PM 亚型激活 TRP 通道的分子和物理化学决定因素。 TRPV1、TRPM8 和其他 PM 感应 TRP 通道也将作为小鼠 PM 毒性介质进行评估。 PM 诱导的肺毒性将使用 TRP 通道拮抗剂和 TRP 通道敲除小鼠进行研究。此外，将识别和验证区分不同 PM 引起的肺部 TRP 通道激活的可量化生物标志物。这些数据将推动未来对在高污染事件中经历呼吸窘迫的人类的研究。拟议的研究将建立 PM 引起的肺毒性的基本机制，并为 PM 引起的呼吸窘迫的机制提供重要见解。未来的研究将尝试将特定 TRP 通道的激活与环境引起的人类呼吸窘迫联系起来。预计这项研究的综合结果将改变未来的生物医学研究，研究呼吸系统疾病和与环境 PM 暴露相关的疾病的起源和治疗策略。公共健康相关性：这项研究将识别和表征肺部蛋白质，这些蛋白质可能会决定一个人在吸入污染空气时是否会出现健康问题。鉴定负责感知和响应吸入空气污染的蛋白质以及发生反应的机制，最终将使科学家和医生能够建立有效的方法来治疗和/或预防因呼吸污染空气而引起的疾病。