application): Background: Acute lung injury is a severe respiratory condition due to its complex etiology and a poor prognosis (i.e. mortality > 40 percent). Currently, questions remain about the mechanism controlling this condition and their relationship to therapeutic strategies. In inbred mice, oxidants can induce alveolar damage with fatal hemorrhagic pulmonary edema that models the exudative phase of acute lung injury. Previously, a 3-fold difference in the mean survival times was noted between two inbred strains, the sensitive A/J and the resistant C57BL/6J. Survival time, a quantitative trait amendable to genetic analysis, was then recorded in offspring from these strains. A genome scan subsequently identified 3 quantitative trait loci (QTLs) with linkage to oxidant-induced acute lung injury (designated Ali 1, 2, and 3) and several possible modifiers on chromosomes 5, 6, and 7. Hypothesis: Resolution of the major genetic determinants of survival during oxidant inhalation (including Ali 1, a major locus on mouse chromosome 11) will provide valuable insights into essential pathological events in acute lung injury.
Specific Aims : 1) To further narrow the QTL interval containing Ali 1 to a level amenable to physical mapping (from > 10 to < 1.0cM), congenic mouse lines will be generated and phenotyped. 2) To concurrently assess candidate genes located in this interval, existing mice with altered gene expression [i.e. gene-targeted (knockout) or expression enhanced (transgenic) mice] will be phenotyped by exposure to ozone. 3) To assess the pathophysiological significance of the identified genetic region, mice with a susceptible phenotype will be rescued using transgenic insertion of artificial chromosomes from contigs containing Ali 1. Significance: This investigation seeks to uncover novel genes not previously associated with survival during acute lung injury. Such findings could provide new biological information and insights into this severe clinical condition.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL065612-04
Application #
6638695
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Harabin, Andrea L
Project Start
2000-07-01
Project End
2005-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
4
Fiscal Year
2003
Total Cost
$302,092
Indirect Cost
Name
University of Cincinnati
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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