Acute lung injury (ALI) and its most severe presentation acute respiratory distress syndrome (ARDS), represent a full spectrum of a complex and devastating illness, with associated mortality hovering at 30-40%. Even supplemental O2, a routine and needed therapy for such patients, paradoxically causes lung injury. In fact, detrimental effects of O2 have established hyperoxic acute lung injury (HALI) as a prototype to study respiratory distress syndromes in experimental animals. To confront the high ALI mortality rate and to assess the genetic complexity of HALI differently than current strategies, we have established a mouse model (sensitive C57BL/6J and resistant 129X1/SvJ mice), with a long-term goal is to identify genes and the related pathologic mechanisms affecting strain survival differences. Segregation analysis of 840 F2 mice generated from the four possible intercrosses between these strains verified that survival time is a complex trait with reduced penetrance, and significant sex, cross, and parent-of-origin effects. Quantitative trait locus (QTL) analyses of the 840 F2 mice identified three highly significant loci (named Shali1-3, for Survival to hyperoxic acute lung injury) and one significant locus (Shali4) in the total F2 population, and a significant male-specific locus (Shali5). Pairwise analysis identified several gene-gene interactions among the QTLs and an epistatic interaction with an otherwise unlinked locus. Segregation and QTL analyses revealed that resistance alleles originate from both parental strains and recombine to determine individual HALI susceptibility. These results have led to the following hypothesis: Shali QTLs contain susceptibility genes that, separately and/or when grouped together in appropriate allelic combinations, will significantly affect HALI survival time. The primary objective of this application is to set the stage for physical mapping and quantitative trait gene identification, with a major focus on Shali1. To accomplish this, we propose 3 Specific Aims: 1) confirm QTL results in vivo by constructing reciprocal congenic strains for the five Shali QTLs significantly linked to HALI survival time in the B-S model;establish which QTL(s) significantly contribute to HALI survival time;2) test candidate genes and reduce the Shali1 QTL interval to a level amenable to physical mapping;prioritize and critically assess candidate genes for functional significance;concurrently, reduce the Shali1 QTL interval by constructing and testing congenic substrains;and 3) determine the best allelic combinations for increased and decreased survival in multi-congenic strains containing the corresponding QTLs in the appropriate strain;generate reciprocal congenics with all four sensitive or all four resistant Shali alleles in the same strain. Mouse lines derived from these studies will give us the needed tools to identify and characterize the key gene(s) affecting HALI survival. PUBLIC HEALTH REVELANCE: Using >95% oxygen (hyperoxia) in our established mouse model, the long-term goal of this project is to identify critical genes involved in acute lung injury survival, which will allow us to focus future efforts on the molecular mechanisms involved. Our previous genetic analyses identified five chromosomal regions significantly linked with survival time;these regions were named Shali1-5, for Survival to hyperoxic acute lung injury loci 1-5. The primary objective of this application is to set the stage for identifying the major gene(s) controlling survival by generating and testing genetically-refined mouse models containing susceptibility alleles in a fixed background.

Public Health Relevance

RESEARCH &RELATED- OTHER PROJECT INFORMATION 7. Project Narrative Using >95% oxygen (hyperoxia) in our established mouse model, the long-term goal of this project is to identify critical genes involved in acute lung injury survival, which will allow us to focus future efforts on the molecular mechanisms involved. Our previous genetic analyses identified five chromosomal regions significantly linked with survival time;these regions were named Shali1-5, for Survival to hyperoxic acute lung injury loci 1-5. The primary objective of this application is to set the stage for identifying the major gene(s) controlling survival by generating and testing genetically-refined mouse models containing susceptibility alleles in a fixed background.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL075562-08
Application #
8251198
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Harabin, Andrea L
Project Start
2003-01-15
Project End
2013-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
8
Fiscal Year
2012
Total Cost
$386,322
Indirect Cost
$128,774
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Zhou, Xiaojing; Fang, Ming; Li, Jiahan et al. (2012) Characterization of genomic imprinting effects and patterns with parametric accelerated failure time model. Mol Genet Genomics 287:67-75
Leikauf, George D; Concel, Vincent J; Liu, Pengyuan et al. (2011) Haplotype association mapping of acute lung injury in mice implicates activin a receptor, type 1. Am J Respir Crit Care Med 183:1499-509
Piao, Zhongze; Zhou, Xiaojing; Yan, Li et al. (2011) Statistical optimization of parametric accelerated failure time model for mapping survival trait loci. Theor Appl Genet 122:855-63
Prows, Daniel R; Hafertepen, Amanda P; Winterberg, Abby V et al. (2007) Genetic analysis of hyperoxic acute lung injury survival in reciprocal intercross mice. Physiol Genomics 30:271-81
Prows, Daniel R; Hafertepen, Amanda P; Gibbons Jr, William J et al. (2007) A genetic mouse model to investigate hyperoxic acute lung injury survival. Physiol Genomics 30:262-70