A genetic mouse model to investigate hyperoxic acute lung injury survival

Prows, Daniel R.; Hafertepen, Amanda P.; Gibbons, William J.; Winterberg, Abby V.; Nick, Todd G.

doi:10.1152/physiolgenomics.00232.2006

Cited by 27 publications

(37 citation statements)

References 39 publications

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“…Transgressive segregation is not uncommon (18,32,34,36) and is most frequently observed in intraspecific crosses involving inbred populations (34). In a QTL mapping study for hyperoxic acute lung injury, a transgressive allele was similarly uncovered as the second strongest locus for the trait (33). This class of genetic variation might be also viewed as cryptic genetic variation (CGV).…”

Section: Discussionmentioning

confidence: 99%

A novel genetic locus modulates infarct volume independently of the extent of collateral circulation

Chu

Keum

Marchuk

2013

Physiological Genomics

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Chu PL, Keum S, Marchuk DA. A novel genetic locus modulates infarct volume independently of the extent of collateral circulation. Physiol Genomics 45: 751-763, 2013. First published June 25, 2013 doi:10.1152/physiolgenomics.00063.2013.-In the mouse model of permanent, middle cerebral artery occlusion, infarct volume varies widely across inbred strains but generally is inversely correlated with collateral vessel number. However, we also observed certain mouse strains that share similar collateral vessel anatomy but exhibit significantly different infarct volume. To identify genetic factors determining infarct volume in a collateral vessel-independent manner, we performed quantitative trait locus analysis on a F2 cross between C57BL/6J and C3H/HeJ strains. We mapped four novel loci (Civq4 through Civq7) that modulate infarct volume. Civq4, on chromosome 8, is the strongest locus (logarithm of the odds 9.8) that contributes 21% of the phenotypic variance of infarct volume in the cross. The Civq4 and Civq6 loci represent transgressive B6 alleles that render animals susceptible to larger infarcts. Based on genomic sequence and microarray analyses, we propose candidate genes for the Civq4 locus. By selecting inbred strains with similar collateral vessel anatomy but that vary significantly in infarct volume, we have mapped four loci determining infarct volume in a mouse model of ischemic stroke. Two of the loci appear to modulate infarct volume through a collateral vessel-independent mechanism. Based on strain-specific sequence variants and differences in transcript levels, Msr1 and Mtmr7 appear to be strong candidate genes for Civq4. Identifying the underlying genetic factors of these loci will elucidate the genetic architecture response to cerebral ischemia, shed new light on disease mechanisms of ischemic stroke, and identify potential therapeutic targets for clinical applications. ischemic stroke; collateral circulation; quantitative trait locus; transgressive segregation; stroke genetics DESPITE ADVANCES IN TREATMENT, cerebrovascular disease (stroke) remains a significant public health issue with ϳ795,000 new cases in the United States each year (35). The majority (87%) of stroke is ischemic in origin, caused by an interruption of blood flow in the cerebral arteries, leading to cerebral infarction (neuronal death). Currently, several genome-wide association studies have discovered genetic risk variants for ischemic stroke, but these studies explain only a small portion of the total genetic risk (6, 29). Moreover, these variants are generally associated with the risk to develop ischemic disease and do not relate to the various stroke outcomes. Stroke outcomes will be particularly difficult to uncover in human populations given the wide variability in the location and extent of the occluded vessel, as well as variation in period of time between the onset of ischemia and medical intervention. Thus, we have proposed to use animal models of ischemic stroke as an alternative to identify genetic factors modifying the is...

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Section: Discussionmentioning

confidence: 99%

A novel genetic locus modulates infarct volume independently of the extent of collateral circulation

Chu

Keum

Marchuk

2013

Physiological Genomics

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“…Ozone, one of the most potent oxidants known (13), quickly produces a pulmonary response in inbred mice that resembles the exudative phase of ARDS; at doses greater than or equal to 4 ppm, ozone causes death within 2 days (14). In contrast to the rapid time course of ozone, nickel (15) and hyperoxia (16,17) can induce ALI mortality within 3 to 4 days in sensitive strains, but resistant strains of mice can survive as long as 10 to 12 days. Importantly, at a time just before their respective mean survival times (MSTs), certain pathologies of ozone-, nickel-, and hyperoxiainduced ALIs are similar in various inbred mouse strains (18,19), suggesting a possible overlap in the injury response to the different oxidants.…”

mentioning

confidence: 99%

Reciprocal Congenic Lines of Mice Capture the Aliq1 Effect on Acute Lung Injury Survival Time

Prows

Hafertepen²,

Winterberg³

et al. 2008

Am J Respir Cell Mol Biol

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Acute lung injury (ALI) is a devastating condition resulting from diverse causes. Genetic studies of human populations indicate that ALI is a complex disease with substantial phenotypic variance, incomplete penetrance, and gene-environment interactions. To identify genes controlling ALI mortality, we previously investigated mean survival time (MST) differences between sensitive A/J (A) and resistant C57BL/6J (B) mice in ozone using quantitative trait locus (QTL) analysis. MST was significantly linked to QTLs (Aliq1-3) on chromosomes 11, 13, and 17, respectively. Additional QTL analyses of separate and combined backcross and F 2 populations supported linkage to Aliq1 and Aliq2, and established significance for previously suggestive QTLs on chromosomes 7 and 12 (named Aliq5 and Aliq6, respectively). Decreased MSTs of corresponding chromosome substitution strains (CSSs) verified the contribution of most QTL-containing chromosomes to ALI survival. Multilocus models demonstrated that three QTLs could explain the MST difference between progenitor strains, agreeing with calculated estimates for number of genes involved. Based on results of QTL genotype analysis, a double CSS (B.A-6,11) was generated that contained Aliq1 and Aliq4 chromosomes. Surprisingly, MST and pulmonary edema after exposure of B.A-6,11 mice were comparable to B mice, revealing an unpredicted loss of sensitivity compared with separate CSSs. Reciprocal congenic lines for Aliq1 captured the corresponding phenotype in both background strains and further refined the QTL interval. Together, these findings support most of the previously identified QTLs linked to ALI survival and established lines of mice to further resolve Aliq1.Keywords: acute respiratory distress syndrome; chromosome substitution strain; congenic; mean survival; pulmonary edema Acute lung injury (ALI), resulting from both pulmonary and extrapulmonary insults (1-3), is a common outcome of diverse injuries. Although painstaking clinical research has investigated an ever-increasing number of viable candidate genes as potential therapeutic targets, little headway has been made to impact the survival rates of patients with ALI or acute respiratory distress syndrome (ARDS), the most severe manifestation of the disease (4-6). A recent report estimated an annual U.S. mortality rate of 74,500/year and 59,000/year for ALI and ARDS, respectively (6).To complement recent studies of ALI/ARDS candidate genes in human populations (7-12), we initiated studies in inbred mice aimed at identifying the genetic factors controlling ALI. Because our long-term goal is to improve mortality rates, survival time from oxidant-induced ALI has been a common theme used as the quantitative trait (phenotype). Ozone, one of the most potent oxidants known (13), quickly produces a pulmonary response in inbred mice that resembles the exudative phase of ARDS; at doses greater than or equal to 4 ppm, ozone causes death within 2 days (14). In contrast to the rapid time course of ozone, nickel (15) and hyperoxia (16, 17) can i...

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“…We selected adult, male mice for this study, because the original investigation that identified Nrf2 as a susceptibility gene for hyperoxiainduced ALI used B6 and C3 mice with this age and gender (7). However, a role of gender in model ALI induced by hyperoxia has been demonstrated as indicated by differential disease susceptibility (29,30,37). We have also found that, although Nrf2 has an important protective role in the neonatal pulmonary response to hyperoxia (11), it was not associated with neonatal susceptibility to hyperoxia as determined in a genome-wide association study with 30 inbred strains of mice (35).…”

Section: Fig 5 Functional Assessment Of Snp Haplotypes In Vivo (A)mentioning

confidence: 74%

Association of Nrf2 Polymorphism Haplotypes with Acute Lung Injury Phenotypes in Inbred Strains of Mice

Cho

Jedlicka

Gladwell

et al. 2015

Antioxidants & Redox Signaling

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Aims: Nrf2 is a master transcription factor for antioxidant response element (ARE)-mediated cytoprotective gene induction. A protective role for pulmonary Nrf2 was determined in model oxidative disorders, including hyperoxia-induced acute lung injury (ALI). To obtain additional insights into the function and genetic regulation of Nrf2, we assessed functional single nucleotide polymorphisms (SNPs) of Nrf2 in inbred mouse strains and tested whether sequence variation is associated with hyperoxia susceptibility. Results: Nrf2 SNPs were compiled from publicly available databases and by re-sequencing DNA from inbred strains. Hierarchical clustering of Nrf2 SNPs categorized the strains into three major haplotypes. Hyperoxia susceptibility was greater in haplotypes 2 and 3 strains than in haplotype 1 strains. A promoter SNP -103 T/C adding an Sp1 binding site in haplotype 2 diminished promoter activation basally and under hyperoxia. Haplotype 3 mice bearing nonsynonymous coding SNPs located in (1862 A/T, His543Gln) and adjacent to (1417 T/C, Thr395Ile) the Neh1 domain showed suppressed nuclear transactivation of pulmonary Nrf2 relative to other strains, and overexpression of haplotype 3 Nrf2 showed lower ARE responsiveness than overexpression of haplotype 1 Nrf2 in airway cells. Importantly, we found a significant correlation of Nrf2 haplotypes and hyperoxic lung injury phenotypes. Innovation and Conclusion: The results indicate significant influence of Nrf2 polymorphisms and haplotypes on gene function and hyperoxia susceptibility. Our findings further support Nrf2 as a genetic determinant in ALI pathogenesis and provide useful tools for investigators who use mouse strains classified by Nrf2 haplotypes to elucidate the role for Nrf2 in oxidative disorders. Antioxid. Redox Signal. 22,[325][326][327][328][329][330][331][332][333][334][335][336][337][338]

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A genetic mouse model to investigate hyperoxic acute lung injury survival

Cited by 27 publications

References 39 publications

A novel genetic locus modulates infarct volume independently of the extent of collateral circulation

A novel genetic locus modulates infarct volume independently of the extent of collateral circulation

Reciprocal Congenic Lines of Mice Capture the Aliq1 Effect on Acute Lung Injury Survival Time

Association of Nrf2 Polymorphism Haplotypes with Acute Lung Injury Phenotypes in Inbred Strains of Mice

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