The overall objectives of the studies in this proposal are to determine the mechanisms of CD14 gene expression and to establish the molecular mechanisms through which single nucleotide polymorphisms confer susceptibility to the allergic phenotype. A polymorphism in the CD14 promoter is associated with alterations in serum soluble CD14 levels and IgE. We have demonstrated that this polymorphism produces changes in CD14 promoter transcriptional activity. In addition, we have identified four additional single nucleotide polymorphisms in the 5'-regulatory region of the CD14 gene that are associated with differences in serum soluble CD14 in the population. The first specific aim is to define the elements of an identified cis-acting silencer of CD14 transcription and to determine the functional interaction of this silencer with genetic polymorphisms. We hypothesize that specific sequences in the silencer element located upstream of the proximal CD14 promoter are responsible for repressive effects on CD14 transcription and that genetic polymorphisms in this region alter DNA/transcription factor interactions and functionally affect transcriptional repression.
The second aim i s to assess the role of chromatin conformation in CD14 gene expression and determine whether genetic polymorphisms at the CD14 locus alter chromatin conformation, DNA accessibility, and CD14 transcriptional activities. We hypothesize that chromatin remodeling is an essential step in the transcriptional activation at the CD14 locus, that hypersensitive sites distinguish critical transcriptional control elements, and that genetic polymorphisms alter the function of promoter distal enhancer elements. An enhanced understanding of these mechanisms will strengthen our ability to comprehend the gene by environment interactions that are involved in the development of asthma related traits. This knowledge will allow the development of preventive and therapeutic strategies for asthma.
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