The long-term goal of our research is to improve care of persons adversely affected by particulate components of air pollution (PM) by elucidating specific molecular pathways that mediate adverse respiratory responses to PM. The immediate goals of this project are to establish the molecular and chemical basis for differential activation of the recently discovered """"""""PM-sensing"""""""" Ca++ channels, TRPA1, V1, and M8, using two representative combustion-derived particles (cdPM): diesel PM (DEP) and coal fly ash (CFA1), to reveal the contributions of these ion channels in determining PM-induced changes in airway cell homeostasis and respiratory function. Our hypothesis is: TRPA1, V1, and M8 are differentially activated by cdPM as a function of its physical/chemical composition, receptor-specific chemo- and mechano-sensing domains, and cellular expression/localization of TRPA1, V1, and M8 channels. Furthermore, activation of TRPA1, V1 and/or M8 by cdPM are pivotal events underlying the pneumotoxic effects of DEP, CFA1, and similar environmental cdPM.
Our specific aims are: 1) pinpoint the regions of TRPA1, V1, and M8 required for activation by DEP and CFA1;2) link TRPA1, V1, and/or M8 activation with specific airway cellular responses to DEP and CFA1;and 3) demonstrate TRPA1, V1, and/or M8 as mediators of pathophysiological responses of lung tissue to DEP and CFA1. The hypothesis and aims of this study are based on fascinating results showing that several PM, including DEP and CFA1, interact with these specific ion channel proteins at the surface of lung cells, and through unique pharmacological mechanisms, regulate discrete cellular and lung responses that underlie commonly observed PM-induced pulmonary morbidities. Our supporting data demonstrate TRPA1 is predominantly, but not exclusively, activated by reactive chemicals released from DEP and another environmentally relevant cdPM;wood smoke PM (WSP), while TRPV1, M8, and to a lesser extent A1, are uniquely activated by mechanical perturbation of cell surface receptor domains by insoluble components of DEP, CFA1, and other model PM. Neuronal stimulation and subsequent reduction in lung compliance elicited by DEP are inhibited by the TRPA1 antagonist HC-030031, and both neurons and bronchial epithelial cells are stimulated by CFA1 via TRPV1, with pro-inflammatory and pro-apoptotic gene induction in lung epithelial cells and lung tissue being largely dependent upon TRPV1 expression and function (i.e., inhibited by the antagonist LJO-328 or in TRPV1-/- mice). Upon completion of the proposed studies, we will provide conclusive evidence that TRPA1, V1, and M8 are specific molecular pathways that link air pollution to commonly observed adverse outcomes in respiratory tissue. This information is essential for both identifying highly sensitive individuals at greatest risk for developing health problems due to air pollution and developing innovative clinical treatments to protect such people from the adverse effects of PM.

Public Health Relevance

Our objective is to elucidate the basis by which environmental particulate pollutants (PM) adversely affect humans such that tests can be developed to identify individuals at greatest risk of PM-induced toxicities and specific and effective medical interventions can be developed to selectively attenuate the adverse effects of PM on human respiratory (and possibly other) health issues. This project will investigate two fundamental questions central to achieving these objectives and to overcoming limitations in our ability to prevent the adverse effects of polluted air in both acute and chronic exposure scenarios. The questions are: 1) what proteins, and molecular features of these proteins, detect different types of PM? and 2) does activation of a specific ion channel by a specific type of PM regulate lung injury, respiratory dysfunction, or even chronic disease? Answers to these questions are critical to understanding the broad health effects linked to environmental PM exposure by population-based studies and for the development of new and effective ways to selectively mitigate the adverse effects of heterogeneous environmental PM in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES017431-05
Application #
8663692
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Nadadur, Srikanth
Project Start
2009-09-17
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Utah
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Deering-Rice, Cassandra E; Nguyen, Nam; Lu, Zhenyu et al. (2018) Activation of TRPV3 by Wood Smoke Particles and Roles in Pneumotoxicity. Chem Res Toxicol 31:291-301
Jaramillo, Isabel C; Sturrock, Anne; Ghiassi, Hossein et al. (2018) Effects of fuel components and combustion particle physicochemical properties on toxicological responses of lung cells. J Environ Sci Health A Tox Hazard Subst Environ Eng 53:295-309
Lamb, John G; Romero, Erin G; Lu, Zhenyu et al. (2017) Activation of Human Transient Receptor Potential Melastatin-8 (TRPM8) by Calcium-Rich Particulate Materials and Effects on Human Lung Cells. Mol Pharmacol 92:653-664
Zhang, Shuwei; Qiu, Yixing; Kakule, Thomas B et al. (2017) Identification of Cyclic Depsipeptides and Their Dedicated Synthetase from Hapsidospora irregularis. J Nat Prod 80:363-370
Deering-Rice, Cassandra E; Stockmann, Chris; Romero, Erin G et al. (2016) Characterization of Transient Receptor Potential Vanilloid-1 (TRPV1) Variant Activation by Coal Fly Ash Particles and Associations with Altered Transient Receptor Potential Ankyrin-1 (TRPA1) Expression and Asthma. J Biol Chem 291:24866-24879
Deering-Rice, Cassandra E; Shapiro, Darien; Romero, Erin G et al. (2015) Activation of Transient Receptor Potential Ankyrin-1 by Insoluble Particulate Material and Association with Asthma. Am J Respir Cell Mol Biol 53:893-901
Rose, Tyler M; Reilly, Christopher A; Deering-Rice, Cassandra E et al. (2014) Inhibition of FAAH, TRPV1, and COX2 by NSAID-serotonin conjugates. Bioorg Med Chem Lett 24:5695-5698
Lin, Zhenjian; Koch, Michael; Abdel Aziz, May Hamdy et al. (2014) Oxazinin A, a pseudodimeric natural product of mixed biosynthetic origin from a filamentous fungus. Org Lett 16:4774-7
Deering-Rice, Cassandra E; Mitchell, Virginia K; Romero, Erin G et al. (2014) Drofenine: A 2-APB Analogue with Greater Selectivity for Human TRPV3. Pharmacol Res Perspect 2:e00062
Fariss, Marc W; Gilmour, M Ian; Reilly, Christopher A et al. (2013) Emerging mechanistic targets in lung injury induced by combustion-generated particles. Toxicol Sci 132:253-67

Showing the most recent 10 out of 17 publications