Oxidative stress contributes to the pathogenesis of many respiratory disorders, including bronchopulmonary dysplasia (BPD), or chronic lung disease in infants. Treatment of BPD often involves respiratory support with high oxygen levels, and oxidant injury is an adverse side effect associated with vascular damage and impaired lung development and function in a subset of infants. Differential susceptibility to BPD is poorly understood and previous studies have demonstrated genetic susceptibility to hyperoxic lung injury in strains of adult inbred mice. Furthermore, genetic polymorphisms in a few candidate genes have been associated with BPD in clinical cohorts; however, specific genetic factors predisposing neonates to oxidant lung injury are poorly understood. The objective of this dissertation was to utilize integrated genetic and genomic approaches to identify predictors of susceptibility to neonatal hyperoxic lung injury. Neonates from 36 strains of inbred mice were screened for lung injury phenotypes in response to 72 hours of 100% oxygen exposure. Phenotypes exhibited heritability and haplotype association mapping identified quantitative trait loci (QTLs) for bronchoalveolar lavage macrophage and neutrophil counts. Underlying candidate susceptibility genes included Chrm2, Mgmt, and Cyp2j6 . Further investigation of Chrm2 by targeted gene deletion confirmed a functional role of Chrm2 and its encoded M2 muscarinic acetylcholine receptor as gene deletion resulted in significantly diminished alveolar hyperpermeability and pathology. Expression QTL (eQTL) and gene expression-phenotype correlation analyses revealed genomic variation in normal postnatal lung development and in response to hyperoxia in inbred neonates. There were 29 cis-eQTLs identified at baseline, and candidate genes included Adam17, Tnfaip2, and Eif2ak2 . There were 23 hyperoxia-responsive cis-eQTLs, and Trim30 , Casp9, and Vcp were candidate genes of biological interest. Further integration of genetic and genomic analyses included gene ontology and pathway analysis, which implicated canonical pathways including mitogen-activated protein kinase and NFκB signaling. Ultimately, novel candidate susceptibility genes were discovered that underlie susceptibility to hyperoxic lung injury and may improve identification of the susceptible neonatal population at risk for developing BPD and provide targets for therapeutic intervention.
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|Advisor:||Kleeberger, Steven R., Peden, David|
|Commitee:||Jaspers, Ilona, Kleeberger, Steven R., Noah, Terry, Peden, David, Wiltshire, Tim|
|School:||The University of North Carolina at Chapel Hill|
|School Location:||United States -- North Carolina|
|Source:||DAI-B 73/11(E), Dissertation Abstracts International|
|Subjects:||Genetics, Toxicology, Surgery, Environmental Health|
|Keywords:||Bronchopulmonary dysplasia, Lung injury, Oxidant injury|
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