TRP Channels and Air Pollution

描述（由申请人提供）：空气微粒污染物（Particulate matter； PM）在环境中无处不在。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暴露于PM有关。目前，在分子和细胞水平上的具体作用机制以及减少人体暴露于PM的有害影响的靶向治疗仍不明确。这在一定程度上是因为将PM的存在转化为有害的分子、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变体可被PM激活。此外，激活与细胞因子/趋化因子基因在体外和肺细胞中的表达增加有关。本研究将探讨TRPV1、TRPM8和其他TRP家族钙通道作为肺中PM的传感器和毒性介质的作用。通过TRP通道的定点诱变和PM的物理化学修饰，将建立不同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通道也将被评估为小鼠PM毒性的介质。将使用TRP通道拮抗剂和TRP通道敲除小鼠研究pm诱导的肺毒性。此外，将鉴定和验证可量化的生物标志物，以区分不同PM在肺中的TRP通道激活。这些数据将推动未来对在高污染期间经历呼吸窘迫的人类进行研究。本研究将建立pm诱导肺毒性的基本机制，并为pm诱导呼吸窘迫的机制提供关键见解。未来的研究将试图将特定TRP通道的激活与环境诱导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，调查与暴露于环境PM相关的呼吸系统疾病和疾病的起源和治疗策略。公共卫生相关性：这项研究将识别和表征肺部的蛋白质，这些蛋白质可能决定一个人在吸入污染空气时是否会出现健康问题。识别负责感知和响应吸入空气污染的蛋白质以及反应发生的机制将最终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。

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.