This resubmitted proposal for a Mentored Quantitative Research Career Development Award will provide John Veranth with funding to combine his combustion and aerosol engineering background with cell biochemistry research under the supervision of Dr. Garold Yost as the sponsor and Dr. Ann Aust as the co-sponsor. The research is motivated by the goal of applying mass transfer and heterogeneous (solid-liquid) reaction analysis techniques from chemical engineering to the study of the interactions of low-solubility inorganic air pollution particles with lung cells. The candidate's research emphasis will be on quantitative analysis of intracellular iron dose as a function of measurable particle characteristics and the correlation of this dose with cytokine signaling responses. Results from computational simulations will be compared with experimental data obtained in cultured cell lines, in fresh lung macrophages, and from whole animal inhalation studies. The study is motivated by the biological hypothesis that ambient particles can deliver an inappropriate dose of redox active transition metals to lung tissues where the metals catalyze the formation of reactive oxygen species, initiating a cascade of cytokine signaling responses. Further, these cytokine signals are proposed as a mechanistic link between air pollution and certain adverse effects in sensitive individuals.
The specific aims are:
aim 1 : Develop, using current literature data, a computational model that predicts the intracellular dose of iron or other transition metals in target cells and airway tissues based on measurable particle characteristics.
Specific aim 2 : Determine the effect of temperature, oxidation, and moisture history on the ability of inorganic particles to release redox-active metals under physiological conditions.
Specific aim 3 : Elucidate the kinetics of key mechanistic steps of particle-induced proinflammatory responses in appropriate lung cells by measuring intracellular iron concentration and selected signaling responses.
Specific aim 4 : Use data obtained from cell culture and whole animal inhalation studies to refine and improve the computational model.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Mentored Quantitative Research Career Development Award (K25)
Project #
5K25ES011281-02
Application #
6702315
Study Section
Environmental Health Sciences Review Committee (EHS)
Program Officer
Shreffler, Carol K
Project Start
2003-02-05
Project End
2007-12-31
Budget Start
2004-01-01
Budget End
2004-12-31
Support Year
2
Fiscal Year
2004
Total Cost
$139,213
Indirect Cost
Name
University of Utah
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Parker, J L; Larson, R R; Eskelson, E et al. (2008) Particle size distribution and composition in a mechanically ventilated school building during air pollution episodes. Indoor Air 18:386-93
Veranth, John M; Cutler, N Shane; Kaser, Erin G et al. (2008) Effects of cell type and culture media on Interleukin-6 secretion in response to environmental particles. Toxicol In Vitro 22:498-509
Veranth, John M; Moss, Tyler A; Chow, Judith C et al. (2006) Correlation of in vitro cytokine responses with the chemical composition of soil-derived particulate matter. Environ Health Perspect 114:341-9
Veranth, John M; Reilly, Christopher A; Veranth, Martha M et al. (2004) Inflammatory cytokines and cell death in BEAS-2B lung cells treated with soil dust, lipopolysaccharide, and surface-modified particles. Toxicol Sci 82:88-96