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Gene-Environment Interactions with Ozone and Non-atopic Asthma

基因-环境与臭氧和非特应性哮喘的相互作用

基本信息

批准号：
10302827
负责人：
Samir Kelada
金额：
$ 24.42万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10302827
关键词：
Address Air Air Pollutants Alleles Applications Grants Asthma Attenuated Backcrossings Bioinformatics Biological Bronchoalveolar Lavage Fluid Candidate Disease Gene Cell Count Cells Child Climate Clinical Research Critiques Data Development Endotoxins Environment Eosinophilia Epidemiology Epithelial Epithelial Cells Exhibits Exposure to Future Gene Expression Genes Genetic Genetic Models Genotype Goals Hour House Dust Mite Allergens Human Hyperplasia Immunity Immunologics Immunologist Inbred Strains Mice Individual Injury Interleukin-13 Interleukin-5 Investigation Laboratory Study Leukocytes Lung Lung diseases Lymphoid Cell Maps Mediating Metaplastic Cell Molecular Mucous body substance Mus Ozone Pathway interactions Phenotype Population Production Quantitative Trait Loci Rattus Recombinant Inbred Strain Research Personnel Signal Transduction Specificity Surveys TSLP gene Testing Work adverse outcome airway epithelium airway hyperresponsiveness airway inflammation asthma exacerbation base cigarette smoke cytokine density eosinophil eosinophilic inflammation epidemiology study experimental study gene environment interaction genetic approach genetic variant genomic locus innate immune mechanisms innovation insight mRNA Expression nonhuman primate novel ozone exposure response single-cell RNA sequencing targeted treatment whole genome

项目摘要

PROJECT SUMMARY Epidemiologic studies have provided evidence that ozone (O3) exposure is associated with the development of asthma, in particular the non-atopic (non-allergic) sub-type. These findings are supported by clinical studies showing that ambient O3 exposure is associated with eosinophilic airway inflammation in non-atopic children. Laboratory studies have shown that O3 exposure causes mucous cell metaplasia/hyperplasia in non-human primates, rats and mice. This includes recent results from our groups demonstrating that classical inbred strains of mice exposed to 0.8 ppm O3 (4 hours/day) for 9 days develop eosinophilic airway inflammation in addition to mucous cell hyperplasia. Thus, data in three species and humans provide strong rationale for studies geared towards understanding the underlying mechanisms of the O3 ® non-atopic asthma association. We take a genetic approach to the question of mechanism. We surveyed strains from the Collaborative Cross (CC) mouse population, a new panel of recombinant inbred strains and identified one strain, CC002, that exhibited much higher levels of eosinophilic inflammation after repeated O3 exposure than any other strain tested to date. O3 exposed CC002 mice also developed mucous cell metaplasia and airway hyper- responsiveness (AHR), two other hallmark phenotypes of asthma. Thus, CC002 provides a new genetic model that we can exploit to identify mechanisms underlying the of O3-induced non-atopic asthma association. In the first Aim, we will test the hypothesis that CC002’s exaggerated response to O3 exposure are due to dysregulated epithelial signaling via alarmins that in turn stimulates type 2 innate lymphoid cells (ILC2s). We will determine if epithelial-derived innate cytokines (IL-1a/b, IL-25, IL-33, TSLP) are increased in O3-exposed CC002 mice compared to non-responder strains, and if neutralization of these cytokines attenuates O3-induced airway inflammation and AHR. Next, we will determine if ILC2 numbers and activation are increased in O3- exposed CC002 mice, and if depletion of ILC2s or inhibition of ILC2-derived cytokines (IL-5, IL-13) ameliorates O3-induced airway inflammation and AHR in CC002 mice. To comprehensively characterize molecular responses to O3 in epithelia, ILC2s, and other leukocytes, we will perform single cell RNA-sequencing. Using this innovative and powerful approach, we will quantify differences in gene expression and cellular composition +/- O3, both within and between strains. We will also examine the specificity of CC002’s response by testing whether this strain exhibits exaggerated responses to other exposures, including endotoxin, cigarette smoke, and house dust mite allergen. In the second aim, we will identify the genetic loci that render CC002 sensitive to O3. We will perform quantitative trait locus mapping to identify chromosomal regions harboring CC002 alleles associated with O3 sensitivity, followed by bioinformatic analyses to identify high priority candidate genes at each locus. In total, our work will reveal mechanisms underlying the association between O3 exposure and the development of non-atopic asthma phenotypes and identify potential pathways to target therapeutically.

项目总结