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.
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