Grantee Research Project Results

Environmental Determinants of Host Defense

EPA Grant Number: R834515C003
Subproject: this is subproject number 003 , established and managed by the Center Director under grant R834515
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Denver Childrens Environmental Health Center - Environmental Determinants of Airway Disease in Children
Center Director: Guo, Yanbing
Title: Environmental Determinants of Host Defense
Investigators: Schwartz, David A.
Current Investigators: Schwartz, David A. , Yang, Ivana , Huber, Jonathan , Oakes, Judy , Eyring, Ken
Institution: Boston University , Harvard University
Current Institution: National Jewish Health , University of Colorado at Denver
EPA Project Officer: Hahn, Intaek
Project Period: September 1, 2009 through August 31, 2014 (Extended to June 21, 2017)
RFA: Children's Environmental Health and Disease Prevention Research Centers (with NIEHS) (2009) RFA Text | Recipients Lists
Research Category: Children's Health , Human Health

Objective:

The overall goal of this project is to understand how and why air pollution alters lung host defense. The environmental, clinical, and biological significance of this project is supported by the following observations. First, air pollution accounts for substantial morbidity and mortality throughout the world, including lung infections and preventable deaths in children. Second, endotoxin is ubiquitous in the environment and is associated with the development and progression of asthma and other forms of airway disease. Third, the ability of the host to respond to lipopolysaccharide and other PAMPs (pathogen associated molecular patterns) is highly variable in mice and humans, yet polymorphic host defense genes only account for a portion of this variable response. Fourth, innate immunity provides a first line of host defense against microbial pathogens that is conserved over a wide variety of species from flies to mammals, and innate immune signaling mechanisms in mice are almost identical to those in humans. Finally, the innate immune system is dynamic biologically, and is responsive to both ozone and PAMPs. We have recently found that the expression of innate immune receptors on macrophages can be enhanced by ozone or PAMPs. Moreover, others have reported that innate immune cells avoid excessive PAMP induced inflammation by downregulating proinflammatory genes while continuing to transcribe antimicrobial genes.

Expected Results:

Thus, the overall hypothesis of this project is that the expression of toll-like receptors (TLRs) in the lung are influenced by environmental (ozone and/or PAMPs) and genetic factors, and the dynamic expression of TLRs has profound effects on lung host defense and consequently the development of lung infections and allergic airway disease. To test this hypothesis, we will pursue the following aims. 1.Determine the effect of in vitro exposures to ozone and/or PAMPs on the expression of TLRs in murine macrophages and dendritic cells. 2.Determine the effect of in vivo exposures to ozone and/or PAMPs on the expression of TLRs in mouse lungs. 3.Determine the effect of in vivo exposures to ozone and/or PAMPs on susceptibility to lung pathogens. 4. Determine the effect of in vivo exposures to ozone and/or PAMPs on house dust mite (HDM) sensitization and the development of HDM induced allergic airway disease in mice.

Publications and Presentations:

Publications have been submitted on this subproject: View all 23 publications for this subproject | View all 51 publications for this center

Journal Articles:

Journal Articles have been submitted on this subproject: View all 14 journal articles for this subproject | View all 30 journal articles for this center

Supplemental Keywords:

Endotoxin, exposure, children, asthma, risk, health effects, susceptibility, sensitive populations, genetic pre-disposition, genetic polymorphism, indoor air, dose-response, ozone, remediation, human health,, Health, Scientific Discipline, HUMAN HEALTH, Health Risk Assessment, Allergens/Asthma, Health Effects, Biology, asthma, asthma triggers, sensitive populations, endotoxin, airway inflammation, children, allergic response

Progress and Final Reports:

Main Center Abstract and Reports:

R834515 Denver Childrens Environmental Health Center - Environmental Determinants of Airway Disease in Children

Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R834515C001 Endotoxin Exposure and Asthma in Children
R834515C002 Environmental Determinants of Early Host Response to RSV
R834515C003 Environmental Determinants of Host Defense

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The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.