Grantee Research Project Results

2000 Progress Report: Genetic Mechanisms of Susceptibility to Inhaled Pollutants

EPA Grant Number: R826724C003
Subproject: this is subproject number 003 , established and managed by the Center Director under grant R826724
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Center for the Study of Childhood Asthma in the Urban Environment
Center Director: Hansel, Nadia
Title: Genetic Mechanisms of Susceptibility to Inhaled Pollutants
Investigators: Kleeberger, Steven R.
Institution: The Johns Hopkins University
EPA Project Officer: Callan, Richard
Project Period: January 1, 1998 through January 1, 2002
Project Period Covered by this Report: January 1, 1999 through January 1, 2000
Project Amount: Refer to main center abstract for funding details.
RFA: Centers for Children's Environmental Health and Disease Prevention Research (1998) RFA Text |  Recipients Lists
Research Category: Children's Health , Human Health

Objective:

This research project will examine the genetic basis for susceptibility to an inflammatory response in airways to reactive oxidant species generated as a result of exposure to ozone. Ozone has been linked to respiratory morbidity in population studies, and it is also apparent that there is marked inter-individual variation in response to ozone exposure in adults and children. Using mouse strains with known susceptibility O3 induced airway inflammation, this project will generate high-resolution linkage maps of the regions of mouse chromosomes 17 and 11 carrying O3 susceptibility loci. Later, we will use comparative mapping approaches to search for homologous human susceptibility loci. We will develop congenic strains of mice that contain the genomic regions that confer differential genetic susceptibility to inflammatory response and epithelial injury. Finally, we will characterize the kinetics of the response to O3 in resistant and -susceptible congenic mouse strains to evaluate the mechanisms through which the susceptibility locus modulates susceptibility. In as much as there is close linkage homology between mouse and human genomes, the identification of genes that control susceptibility to O3 in this model may provide a means to characterize individuals in human populations who are at risk to oxidant exposures. The community-based studies in this Center will seek to relate ozone exposure to asthma morbidity, and will have developed relationship with families of asthmatic children in the community to allow us to plan genetic studies of pollutant response.

Progress Summary:

This research project examined the genetic basis for susceptibility to an inflammatory response in airways to reactive oxidant species generated as a result of exposure to ozone. Ozone has been linked to respiratory morbidity in population studies, and it is also apparent that there is marked inter-individual variation in response to ozone exposure in adults and children. Using mouse strains with known susceptibility O3 induced airway inflammation, this project will generate high-resolution linkage maps of the regions of mouse chromosomes 17 and 11 carrying O3 susceptibility loci. The investigators are using comparative mapping approaches to search for homologous human susceptibility loci. They will develop congenic strains of mice that contain the genomic regions that confer differential genetic susceptibility to inflammatory response and epithelial injury. Finally, they will characterize the kinetics of the response to O3 in resistant and -susceptible congenic mouse strains to evaluate the mechanisms through which the susceptibility locus modulates susceptibility. In as much as there is close linkage homology between mouse and human genomes, the identification of genes that control susceptibility to O3 in this model may provide a means to characterize individuals in human populations who are at risk to oxidant exposures. The community-based studies in this Center will seek to relate ozone exposure to asthma morbidity, and will have developed relationship with families of asthmatic children in the community to allow researchers to plan genetic studies of pollutant response.

Future Activities:

This research project will continue to examine the genetic basis for susceptibility to an inflammatory response in airways to reactive oxidant species generated as a result of exposure to ozone. Ozone has been linked to respiratory morbidity in population studies, and it is also apparent that there is marked inter-individual variation in response to ozone exposure in adults and children. Using mouse strains with known susceptibility O3 induced airway inflammation, this project will generate high-resolution linkage maps of the regions of mouse chromosomes 17 and 11 carrying O3 susceptibility loci. Later, the investigators will use comparative mapping approaches to search for homologous human susceptibility loci. They will develop congenic strains of mice that contain the genomic regions that confer differential genetic susceptibility to inflammatory response and epithelial injury. Finally, they will characterize the kinetics of the response toO3in resistant and -susceptible congenic mouse strains to evaluate the mechanisms through which the susceptibility locus modulates susceptibility. In as much as there is close linkage homology between mouse and human genomes, the identification of genes that control susceptibility toO3 in this model may provide a means to characterize individuals in human populations who are at risk to oxidant exposures. The community-based studies in this Center will seek to relate ozone exposure to asthma morbidity, and will have developed relationship with families of asthmatic children in the community to allow researchers to plan genetic studies of pollutant response.

Supplemental Keywords:

Health, RFA, Scientific Discipline, Allergens/Asthma, Atmospheric Sciences, Biochemistry, Children's Health, Disease & Cumulative Effects, Ecological Risk Assessment, Epidemiology, Health Risk Assessment, Risk Assessments, Human Health Risk Assessment, age-related differences, air pollutants, air pollution, air toxics, airborne pollutants, airborne urban contaminants, airway disease, airway inflammation, ambient particulates, asthma, asthma morbidity, asthmatic children, children, children's environmental health, community based, community-based intervention, disease, environmental health, epidemelogy, epidemeology, health effects, human exposure, human health risk, morbidity, RFA, Health, Air, Scientific Discipline, Susceptibility/Sensitive Population/Genetic Susceptibility, Health Risk Assessment, Risk Assessments, Chemistry, particulate matter, Biology, genetic susceptability, Environmental Chemistry, Allergens/Asthma, Children's Health, Genetics, community based, childhood respiratory disease, disease, health effects, Human Health Risk Assessment, genetic mechanisms, inhaled, air quality, environmental hazard exposures, genetic predisposition, sensitive populations, inhaled pollutants, airway inflammation, asthma, allergen, biological response, community-based studies, respiratory, cellular biology, human exposure, morbidity, susceptibility, environmental health effects, allergens, children, airway epithelial cells, ozone induced airway dysfunction, particulates, exposure, PM, environmental health hazard, ozone, toxics, analytical chemistry, air pollution, assessment of exposure, community-based intervention, human health effects, inhalation

Relevant Websites:

"A Randomized, Controlled Trial of Home Exposure Control in Asthma"
https://cfpub.epa.gov/ncer_abstracts/index.cfm/fuseaction/display.abstractDetail/abstract/1081

"Mechanisms Of Particulate-Induced Allergic Asthma"
https://cfpub.epa.gov/ncer_abstracts/index.cfm/fuseaction/display.abstractDetail/abstract/1082

"Genetic Mechanisms of Susceptibility to Inhaled Pollutants"
https://cfpub.epa.gov/ncer_abstracts/index.cfm/fuseaction/display.abstractDetail/abstract/1083

Progress and Final Reports:

Original Abstract

1998

1999

Final

Main Center Abstract and Reports:

R826724    Center for the Study of Childhood Asthma in the Urban Environment

Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R826724C001 A Randomized, Controlled Trial of Home Exposure Control in Asthma
R826724C002 Mechanisms Of Particulate-Induced Allergic Asthma
R826724C003 Genetic Mechanisms of Susceptibility to Inhaled Pollutants
R826724C004 The Relationship Of Airborne Pollutants And Allergens To Asthma Morbidity