Genetic analysis of hyperoxic acute lung injury survival in reciprocal intercross mice

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

doi:10.1152/physiolgenomics.00038.2007

Cited by 27 publications

(43 citation statements)

References 46 publications

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“…Backcrosses were also combined based on similar genotypes (i.e., the four group B backcrosses vs. the four group S backcrosses). The importance of the group B and S pairings was suggested by previous findings demonstrating that resistance genes were present in both parental strains (32). MSTs of group B backcrosses differed from group S backcrosses (P ϭ 0.009).…”

Section: Confirmation Of Major Loci For Hali Survival Timementioning

confidence: 86%

“…To assess linkage in the individual and combined backcross groups and to screen for global gene-gene interactions in the group B and S backcross populations, all 935 backcross mice were typed for 78 polymorphic microsatellite markers distributed at 20-to 25-cM intervals across the 19 autosomes; all markers were selected from the total set previously typed in the large F 2 study (32). In addition, all mice were screened with four X chromosome (Chr) markers to assess whether the sex effect might be due to X Chr linkage.…”

Section: Linkage Analysis and Qtl Mappingmentioning

confidence: 99%

“…Solid lines between crosses represent statistical differences in MSTs (P Ͻ 0.05 by ANOVA with Sidak correction); dashed lines represent no differences between MSTs of offspring from the compared crosses. Because F2 and backcross mice were frequently exposed in the same chambers, most of the B and S control mice reported herein were also included in the previous reports on F2 mice (32,33). Sex effects were tested within each group using nested models based on log survival times, with Sidak adjustments.…”

Section: Cross Comparisonsmentioning

confidence: 99%

“…To further investigate this parent of origin difference, a large F 2 population (n ϭ 840 mice) was produced, consisting of 197 or more mice from each of the four possible intercrosses between B and S inbred mice. QTL analysis of the total F 2 population identified five genomic regions (i.e., QTLs) significantly linked to HALI survival time, designated survival to hyperoxic acute lung injury 1-5 (Shali1-5) (32). Additional genetic analyses of F 2 subpopulations identified significant sex, cross, and parent of origin effects on HALI survival time and demonstrated that a further increase in HALI survival time was due to a recombination of resistance alleles originating from both parental strains.…”

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confidence: 99%

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Reciprocal backcross mice confirm major loci linked to hyperoxic acute lung injury survival time

Prows

Winterberg

Gibbons

et al. 2009

Physiological Genomics

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Prows DR, Winterberg AV, Gibbons WJ Jr, Burzynski BB, Liu C, Nick TG. Reciprocal backcross mice confirm major loci linked to hyperoxic acute lung injury survival time. Physiol Genomics 38: 158 -168, 2009. First published May 5, 2009 doi:10.1152/physiolgenomics.90392.2008.-Morbidity and mortality associated with acute lung injury (ALI) and acute respiratory distress syndrome remain substantial. Although many candidate genes have been tested, a clear understanding of the pathogenesis is lacking, as is our ability to predict individual outcome. Because ALI is a complex disease, single gene approaches cannot easily identify effectors that must be treated concurrently. We employed a strategy to help identify critical genes and gene combinations involved in ALI mortality. Using hyperoxia to induce ALI, a mouse model for genetic analyses of ALI survival time was identified: C57BL/6J (B) mice are sensitive (i.e., die early), whereas 129X1/SvJ (S) mice are significantly more resistant, but with low penetrance. Segregation analysis of reciprocal F2 mice generated from B and S strains revealed significant sex, cross, and parent of origin effects. Quantitative trait locus (QTL) analysis identified five chromosomal regions significantly linked to hyperoxic ALI survival time . Further analyses demonstrated that both parental strains contribute resistance alleles to their offspring and that the phenotype demonstrated parent of origin effects. To validate earlier findings, we generated and tested mice from all eight possible B-S-derived backcrosses. Results from segregation and QTL analyses of 935 backcrosses, alone and combined with the previous 840 B-S-derived F2 population, further supported the highly significant QTLs on chromosomes 1 (Shali1) and 4 (Shali2) and confirmed that the sex, cross, and parent of origin all contribute to survival time with hyperoxic ALI. adult respiratory distress syndrome; mouse model; parent of origin effects; quantitative trait locus DESPITE SIGNIFICANT ADVANCES in supportive care and improvements in ventilator management (1), acute lung injury (ALI) and adult respiratory distress syndrome (ARDS) are still associated with 30 -45% mortality, which accounts for nearly 75,000 deaths/yr in the United States (36). Although more than four decades since its first description (2), the persistent high death rate related to ALI/ARDS continues to be a formidable challenge. Even results from recent meta-analyses have been contradictory as to whether ALI/ARDS mortality rates have changed over the last 15 yr (29,50). Although anyone at any age can die after the development and progression of ALI/ ARDS, older patients have an increased risk of dying (36,39,40,51). Accordingly, as the population gets older, the future social and healthcare burdens surrounding ALI will continue to escalate. Consequently, alternative research strategies are needed to address this unremitting problem.The pathophysiology of ALI has been described in detail (11,18,24,25,45,46), yet little is known about the critical genes or gene ...

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Section: Confirmation Of Major Loci For Hali Survival Timementioning

confidence: 86%

Section: Linkage Analysis and Qtl Mappingmentioning

confidence: 99%

Section: Cross Comparisonsmentioning

confidence: 99%

mentioning

confidence: 99%

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Reciprocal backcross mice confirm major loci linked to hyperoxic acute lung injury survival time

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Winterberg

Gibbons

et al. 2009

Physiological Genomics

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“…Primer pairs, chosen based on known polymorphisms between the BALB/cJ and DBA/2J progenitor strains, were purchased from IDT (Coralville, IA). PCR was performed in 15 l in 96-well plates (Applied Biosystems, Foster City, CA), as described previously (51).…”

Section: Methodsmentioning

confidence: 99%

Multigenic Control and Sex Bias in Host Susceptibility to Spore-Induced Pulmonary Anthrax in Mice

et al. 2011

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Mechanisms underlying susceptibility to anthrax infection are unknown. Using a phylogenetically diverse panel of inbred mice and spores of Bacillus anthracis Ames, we investigated host susceptibility to pulmonary anthrax. Susceptibility profiles for survival time and organ pathogen load differed across strains, indicating distinct genetic controls. Tissue infection kinetics analysis showed greater systemic dissemination in susceptible DBA/2J (D) mice but a higher terminal bacterial load in resistant BALB/cJ (C) mice. Interestingly, the most resistant strains, C and C57BL/6J (B), demonstrated a sex bias for susceptibility. For example, BALB/cJ females had a significantly higher survival time and required 4-fold more spores for 100% mortality compared to BALB/cJ males. To identify genetic regions associated with differential susceptibility, survival time and extent of organ infection were assessed using mice derived from two susceptibility models: (i) BXD advanced recombinant inbred strains and (ii) F2 offspring generated from polar responding C and D strains. Genomewide analysis of BXD strain survival identified linkage on chromosomes 5, 6, 9, 11, and 14. Quantitative trait locus (QTL) analysis of the C؋DF2 population revealed a significant QTL (designated Rpai1 for resistance to pulmonary anthrax infection, locus 1) for survival time on chromosome 17 and also identified a chromosome 11 locus for lung pathogen burden. The striking difference between genome-wide linkage profiles for these two mouse models of anthrax susceptibility supports our hypothesis that these are multigenic traits. Our data provide the first evidence for a differential sex response to anthrax resistance and further highlight the unlikelihood of a single common genetic contribution for this response across strains.Anthrax is one of the most ancient and lethal human diseases caused by the virulent (toxigenic and encapsulated) strains of Bacillus anthracis. In humans, anthrax may take three forms depending upon the route of infection, namely, pulmonary (inhalational), cutaneous, and gastrointestinal, with pulmonary being the most lethal and difficult to treat. While the naturally acquired pulmonary anthrax is relatively rare (occurring only ϳ5% as often as cutaneous anthrax), this form has a high potential for misuse as a weapon of bioterrorism, considering that environmental dissemination is the most expected mode of release of the agent in mass attacks (26). Pulmonary anthrax often proves fatal, with mortality approaching 100% if not treated early. Anthrax spores have long been considered a potential agent of biological warfare (25, 50, 58). Prior to the 11 cases of pulmonary anthrax that occurred via the U.S. mail delivery system in 2001 (29), fatal cases of pulmonary anthrax in the United States and other countries have been associated with occupational and accidental exposures (37,60). But the bioterrorism attack in 2001 exposed a new cause for serious concern for future and more widespread attacks on military and civilian populations.The ...

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Inorganic Compounds of Carbon, Nitrogen, and Oxygen

Leikauf,

Bein,

Prows

2023

Patty's Toxicology

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This chapter reviews the toxicology of some of the most commonly encountered chemicals in environmental and occupational settings. Although these chemicals are often generated by industrial processes such as combustion, several are generated by natural processes including endogenous production within the body. These substances are basic to the biological process and therefore life itself. Nonetheless, excessive exposures can be life‐threatening and must be controlled. This chapter is modeled after the excellent, previous chapter in this series written by Michael J. Lipsett, Dennis J. Shusterman, and Rodney R. Beard.

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Genetic analysis of hyperoxic acute lung injury survival in reciprocal intercross mice

Cited by 27 publications

References 46 publications

Reciprocal backcross mice confirm major loci linked to hyperoxic acute lung injury survival time

Reciprocal backcross mice confirm major loci linked to hyperoxic acute lung injury survival time

Multigenic Control and Sex Bias in Host Susceptibility to Spore-Induced Pulmonary Anthrax in Mice

Inorganic Compounds of Carbon, Nitrogen, and Oxygen

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