Acute lung injury is a severe respiratory condition with multiple etiological factors and a poor prognosis (estimates of mortality range from 40 to 60 percent). Numerous precipitating factors have been identified, yet questions remain about the pathophysiological mechanisms controlling this complex condition; thus therapeutic approaches are mainly limited to supportive measures. Nickel sulfate induces alveolar macrophage activation and epithelial disruption that models the exudative phase of acute lung injury. To further develop this model the histopathology and the temporal patterns of co-regulated gene expression (cDNA microarray analysis) was assessed. Acute lung injury progressed leading to death at nickel sulfate concentrations (greater than or equal to 15 mug/m3) below the current occupational limit (100 mug/m3). A 2-fold difference in survival times of two inbred strains, the sensitive A/J (A) and the resistant C57BL/6J (B6), allowed an initial characterization of the genetic loci controlling the survival time phenotype. A quantitative trait locus (QTL) analysis identified a new major locus (proposed as Aliq4 for Acute lung injury qt14) and four modifying loci. This led to the following hypothesis: Further resolution of the major genetic determinants of survival during nickel sulfate inhalation (i.e. Aliq4, a quantitative trait with a major locus on mouse chromosome 6, and four modifier loci) will provide valuable insights into the key pathological events in acute lung injury. To further determine the genetic factors and pathologic mechanisms of acute lung injury, the Specific Aims are: (1.) To further narrow the QTL interval containing Aliq4 and its four modifier loci to a level amenable to physical mapping (i.e. less than 1.0 cM, congenic mouse lines will be generated and phenotyped. (2.) To concurrently assess candidate genes located in the Aliq4 interval, existing mice with altered gene expression [i.e. gene-targeted (knockout) or expression enhanced (transgenic) mice] will be phenotyped by exposure to nickel sulfate. (3.) To determine and verify the pathophysiologically significant region of Aliq4, susceptible mice will be rescued using transgenic insertion of artificial chromosomes containing distinct segments of the Aliq4 interval. Mice (including inbred, congenic, transgenic, and gene targeted strains) offer several advantages to determine genetic traits controlling human conditions. Determination of the relative roles of the genetic loci linked to nickel sulfate exposure is likely to improve our understanding of the mechanisms involved in acute lung injury.
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