Acute lung injury is a common and devastating illness that occurs in the context of sepsis and other systemic inflammatory disorders. Whether a clear genetic basis exists for susceptibility to sepsis, acute lung injury, and ventilator-induced lung injury remains unresolved. To address this critical question, we propose to employ high throughput genomic technologies to examine (i) the patterns of gene expression and (ii) candidate gene polymorphisms which explain susceptibility to ALl. SA #1will prioritize novel sepsis and sepsis/VALI candidate genes obtained by extensive temporal expression profiling conducted in conjunction with Project #1 personnel in a small, well phenotyped subset of patients with sepsis and ALl. These patterns of expression will be analyzed within each clinical and experimental condition, within each species and then across species. This approach will allow us to determine both concordantly and discordantly regulated gene clusters, link these gene clusters with physiological measurements of lung function, and determine the gene profiles responsible for the development and maintenance of either resistance or susceptibility to VALI. SA #2 will then validate the physiological importance of these genes and """"""""high risk"""""""" alleles in a large cohort of well phenotyped patients with sepsis/ALl. We will perform high throughput genotyping for positional candidate genes generated from a combination of (1) human and animal cDNA microarray expression profiles; (2) preliminary data; and (3) literature. In SA #3, we will determine whether the frequencies of functional polymorphisms associated with ALl and sepsis vary significantly in African Americans compared to Caucasians. For any """"""""high risk"""""""" alleles/genotypes/haplotypes identified in Specific Aim 2, frequencies will be obtained from the two population-based samples to test the hypothesis that the prevalence of these allelic variants differs according to ethnicity. Additional analyses will include associations between sepsis and 'no sepsis', regardless of ALl status, and associations between survivors of VALI and non-survivors (e.g. mortality resulting from VALI). We will utilize standard and novel haplotype analytical tools to specifically identify haplotypes, which address the enhanced morbidity and mortality from sepsis and sepsis/VALI. We will rely upon public SNP data as well as the development of novel SNPs. Priority will be given to polymorphisms in coding or regulatory regions.
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