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Functional Genomic Assessment of Ammonia-Induced Acute Lung Injury in Mice
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A2261 - Functional Genomic Assessment of Ammonia-Induced Acute Lung Injury in Mice
Author Block: G. D. Leikauf1, T. Martin1, K. Ganguly2, K. Bein1, V. Concel1, K. A. Brant1, Y. Di1, S. Upadhyay2, J. Fabisiak1; 1Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, United States, 2Karolinska Institute, Stockholm, Sweden.
In this study, a genetically-diverse panel of 43 mouse strains (n= 10 mice/strain) were exposed to 1,500 ppm ammonia (up to 24h), survival time phenotyped, and genome-wide association mapping was performed employing a high density single nucleotide polymorphism (SNP) assembly. Transcriptomic analysis was used to improve the genetic resolution in the identification of genetic determinants of ammonia-induced acute lung injury. We prioritized the identified genes based on whether the encoded protein: (a) had a molecular function related to pulmonary edema and inflammation, (b) contained a nonsynonymous SNP within a functional domain, or (c) contained a promoter SNP that could alter a putative transcription factor binding site and had variable expression by transcriptomic analyses. The latter 2 criteria also required that ≥10% of mice carried the minor allele and that this allele could account for ≥10% of the phenotypic difference noted between the strains at the phenotypic extremes. The most sensitive JF1/Msf strain was approximately 8 times more sensitive than resistant LG/J strain. Because more is known about the genome of sensitive BALB/cJ (mean survival time: 11.7 + 0.8 h) and resistant DBA/2J mouse strains (mean survival time: 38.3 + 3.5 h) theses strains were selected for further analysis. The sensitive BALB/cJ and resistant DBA/2J mouse strains were either exposed to filtered air (control) or to ammonia (1,500 ppm for 11 h), anesthetized, and lung tissue was examined. Consistent with ammonia-induced acute lung injury, pulmonary edema was more evident in the sensitive BALB/cJ strain than in the resistant DBA/2J strain. This integrative functional genomic approach revealed candidate genes that included Cep162, Hrh4, Lama3, Avil, Kcnj1, Plcb4, Ube2cbp, which had significant SNP associations, and Aff1, Bcar3, Cntn4, Kcnq5, Prdm10, Ptcd3, and Snx19, which had suggestive SNP associations. Of these associations Aff1, Bcar3, Cep162, Hrh4, Kcnq5, and Lama3 are particularly noteworthy and had pathophysiologic roles that could be associated with acute lung injury.
Author Block: G. D. Leikauf1, T. Martin1, K. Ganguly2, K. Bein1, V. Concel1, K. A. Brant1, Y. Di1, S. Upadhyay2, J. Fabisiak1; 1Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA, United States, 2Karolinska Institute, Stockholm, Sweden.
In this study, a genetically-diverse panel of 43 mouse strains (n= 10 mice/strain) were exposed to 1,500 ppm ammonia (up to 24h), survival time phenotyped, and genome-wide association mapping was performed employing a high density single nucleotide polymorphism (SNP) assembly. Transcriptomic analysis was used to improve the genetic resolution in the identification of genetic determinants of ammonia-induced acute lung injury. We prioritized the identified genes based on whether the encoded protein: (a) had a molecular function related to pulmonary edema and inflammation, (b) contained a nonsynonymous SNP within a functional domain, or (c) contained a promoter SNP that could alter a putative transcription factor binding site and had variable expression by transcriptomic analyses. The latter 2 criteria also required that ≥10% of mice carried the minor allele and that this allele could account for ≥10% of the phenotypic difference noted between the strains at the phenotypic extremes. The most sensitive JF1/Msf strain was approximately 8 times more sensitive than resistant LG/J strain. Because more is known about the genome of sensitive BALB/cJ (mean survival time: 11.7 + 0.8 h) and resistant DBA/2J mouse strains (mean survival time: 38.3 + 3.5 h) theses strains were selected for further analysis. The sensitive BALB/cJ and resistant DBA/2J mouse strains were either exposed to filtered air (control) or to ammonia (1,500 ppm for 11 h), anesthetized, and lung tissue was examined. Consistent with ammonia-induced acute lung injury, pulmonary edema was more evident in the sensitive BALB/cJ strain than in the resistant DBA/2J strain. This integrative functional genomic approach revealed candidate genes that included Cep162, Hrh4, Lama3, Avil, Kcnj1, Plcb4, Ube2cbp, which had significant SNP associations, and Aff1, Bcar3, Cntn4, Kcnq5, Prdm10, Ptcd3, and Snx19, which had suggestive SNP associations. Of these associations Aff1, Bcar3, Cep162, Hrh4, Kcnq5, and Lama3 are particularly noteworthy and had pathophysiologic roles that could be associated with acute lung injury.
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