Relevance: The goal of this project is to determine the role of oxidative stress in determing the ability of different particles to cause inflammation in the airways and why some individuals are far more susceptible to the adverse effects of particles than others. The ability of diesel exhaust particles (DEP), a major constituent of particulate matter (PM), to exacerbate and initiate allergic airway disease is now firmly established. While other particles can have similar effects, their potency can vary considerably. The central hypothesis to be tested in this study is that oxidative stress is the key mechanism by which DEP and ambient PM induce these pro-inflammatory effects in the human respiratory tract. We propose that responsiveness to PM is determined by the equilibrium between injuryprovoking oxidative stress and the antioxidant/anti-inflammatory effects of Phase II enzymes that normally protect the airways. Moreover, we propose that differences in this equilibrium can explain why some individuals are more susceptible to the adverse effects of PM than others. Oxidative stress in the respiratory tract is a natural consequence of inflammation in these diseases. A hierarchical model has been proposed in which at low levels of oxidative stress, an antioxidant response predominates and as the oxidative stress levels increase, yields to pro-inflammatory responses. We will use our established human nasal exposure model in already identified cohorts of high and low DEP responders to test the validity of the hierarchical oxidative stress model in vivo by studying these responses to PM with strong (ultrafine particles from ambient concentrated air), moderate (fine particles from ambient concentrated air) and weak (inert carbon black) intrinsic abilities to generate oxidative stress:
In Aim 1 we will test the hypothesis that the intrinsic ability of different types of ambient PM to induce reactive oxygen species determines nasal inflammatory responses in humans.
In Aim 2 we will test the hypothesis that the intrinsic ability of defined high and low responder individuals to generate antioxidant/anti-inflammatory responses determines the level of their PM driven nasal and peripheral blood monocyte inflammatory responses.
In Aim 3, we will study the genetic basis for PM susceptibility in humans and test the hypothesis that gene and protein expression profiles differ between high vs. low DEP responders by performance of gene expression networks and proteomics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI070453-04
Application #
7888355
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
4
Fiscal Year
2009
Total Cost
$281,703
Indirect Cost
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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