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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES015056-07
Application #
8300949
Study Section
Special Emphasis Panel (ZES1-JAB-C (ON))
Program Officer
Kirshner, Annette G
Project Start
2006-09-01
Project End
2013-10-31
Budget Start
2012-08-01
Budget End
2013-10-31
Support Year
7
Fiscal Year
2012
Total Cost
$94,261
Indirect Cost
$37,306
Name
Yale University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Gui, Junhong; Liu, Boyi; Cao, Guan et al. (2014) A tarantula-venom peptide antagonizes the TRPA1 nociceptor ion channel by binding to the S1-S4 gating domain. Curr Biol 24:473-83
Liu, Boyi; Escalera, Jasmine; Balakrishna, Shrilatha et al. (2013) TRPA1 controls inflammation and pruritogen responses in allergic contact dermatitis. FASEB J 27:3549-63
Liu, Boyi; Fan, Lu; Balakrishna, Shrilatha et al. (2013) TRPM8 is the principal mediator of menthol-induced analgesia of acute and inflammatory pain. Pain 154:2169-77
Jordt, Sven-Eric (2011) Trigeminal TRPs and the scent of pain. Pain 152:4-5
Willis, Daniel N; Liu, Boyi; Ha, Michael A et al. (2011) Menthol attenuates respiratory irritation responses to multiple cigarette smoke irritants. FASEB J 25:4434-44
Bessac, Bret F; Jordt, Sven-Eric (2010) Sensory detection and responses to toxic gases: mechanisms, health effects, and countermeasures. Proc Am Thorac Soc 7:269-77
Lanosa, Michael J; Willis, Daniel N; Jordt, Sven et al. (2010) Role of metabolic activation and the TRPA1 receptor in the sensory irritation response to styrene and naphthalene. Toxicol Sci 115:589-95
Bessac, Bret F; Sivula, Michael; von Hehn, Christian A et al. (2009) Transient receptor potential ankyrin 1 antagonists block the noxious effects of toxic industrial isocyanates and tear gases. FASEB J 23:1102-14
Caceres, Ana I; Brackmann, Marian; Elia, Maxwell D et al. (2009) A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma. Proc Natl Acad Sci U S A 106:9099-104
Escalera, Jasmine; von Hehn, Christian A; Bessac, Bret F et al. (2008) TRPA1 mediates the noxious effects of natural sesquiterpene deterrents. J Biol Chem 283:24136-44

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