TRP Channels and Air Pollution

描述（由申请人提供）：颗粒空气污染物（颗粒物; 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PM的短期和长期暴露有关。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明确。这部分是因为将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，TRPV 1和TRPM 8变体被PM激活。此外，激活与体外和肺中肺细胞的细胞因子/趋化因子基因表达增加相关联。这项研究将研究TRPV 1，TRPM 8和其他TRP家族钙通道作为PM传感器和肺毒性介质。将使用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。TRPV 1、TRPM 8和其他PM敏感TRP通道也将作为小鼠中PM毒性的介质进行评价。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，将鉴定和验证通过不同PM区分肺中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。该研究将建立PM诱导的肺毒性的基本机制，并为PM诱导的呼吸窘迫机制提供关键见解。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：这项研究将确定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响应发生的机制，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。

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.