Population-based and epidemiological studies have demonstrated significant associations between exposures to the pro-inflammatory oxidant pollutant zone (O3) and exacerbation of asthma, pulmonary function deficits, and school absenteeism in children. Because of the impact that oxidant exposures may have on the health of children and adults, identification of the intrinsic (host) factors that influence susceptibility to airborne pollutants remains an important issue. The potential contribution of genetic background as a host factor for susceptibility to oxidant air pollutants has been strongly suggested but the nature of the genetic control is still unclear. OVERALL OBJECTIVE. To utilize positional cloning and breeding techniques to identify the gene or genes that determine differential susceptibility to O3-induced pulmonary inflammation and injury in inbred strains of mice and search for homologues in the human genome. SPECIFIC OBJECTIVES. We have designed four specific aims.
In Aim 1, we will generate high-resolution linkage maps for susceptibility to O3- induced airways inflammation/epithelial injury.
In Aim 2, we will construct high-resolution long-range physical maps of the regions of mouse chromosomes 17 and 11 carrying O3 susceptibility loci. We will utilize comparative mapping approaches to search for homologous human susceptibility loci.
In Aim 3, we will develop congenic strains of mice that contain the genomic regions that confer differential susceptibility to inflammatory response/epithelial injury. Finally, in Aim 4 we will characterize the kinetics of lung response to in 03-resistant and - susceptible congenic mouse strains to evaluate the mechanisms through which the susceptibility locus modulates differential susceptibility.
. This proposal utilizes a multi-disciplinary approach that will provide unique insight into the genetic mechanisms that determine differential susceptibility to O3-induced inflammation. Inasmuch as there is close linkage homology and conserved synteny between the 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, and potential novel strategies for intervention.
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