TRPA1 Channels in Sensory Neurons as Targets for Environmental Irritants

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): The long term goal of our research is to reveal the molecular and cellular basis of sensory neural activation by hazardous environmental irritants. Sensory nerve endings in the lung, skin, eyes and mucous membranes are activated by environmental toxicants, including the alpha, beta-unsaturated aldehydes. Aldehydes such as acrolein (2-propenal) are severely irritating volatile compounds present in cigarette smoke, smoke from fires, automobile exhaust, and smog. In humans, acrolein exposure has been implicated in the pathogenesis of acute lung injury, chemical hypersensitivity, chronic pulmonary obstructive disease (COPD), and asthma. Despite its important role in human exposure health effects, the molecular targets of acrolein and other environmental irritants on sensory neurons remain unknown. Here, we propose to identify and characterize the molecular targets for acrolein and other environmental irritants on somatosensory neurons. Our specific aims are derived from our preliminary data that show that acrolein, and a different class of irritants, the isocyanates, activate neurons by stimulating Ca2+ influx through the ion channel TRPA1. TRPA1 recently has been identified through its sensitivity to allyl isothiocyanate (mustard oil), an irritant used to probe pain transduction pathways. We found that TRPA1 is exclusively expressed in sensory fibers that are also sensitive to capsaicin, the plant-derived irritant that activates the capsaicin receptor, TRPV1. These sensory fibers, the C-fibers, are known to mediate irritant effects and inflammatory pain. The objective of our application is to investigate whether TRPA1 is underlying acute and long-term irritant effects of acrolein and other environmental exposures in vivo. Our specific aims are to 1) investigate sensory neural responses to acrolein in TRPA1-deficient mice, 2) to elucidate the mechanism of activation and inflammatory sensitization of TRPA1, 3) study and compare the effects of industrial isocyanates on sensory neural activity, and 4) examine the effects of hazardous environmental toxicants on sensory neural activity and sensory neural receptors. Our experimental approaches will include the generation and analysis of transgenic mice, microscopic imaging of neural function, electrophysiological techniques and genetic and biochemical approaches.