Long term objectives are: 1) to understand mechanisms of genes and processes involved in neonatal lung disease in order to help identify specific targets for therapeutic intervention; and 2) to use genetic markers to identify prematurely born infants at risk for acute lung disease who would best respond to a targeted therapy early in their course of treatment or that could make good subjects in future novel drug/therapy trials. Surfactant protein (SP) genetic variants and low levels of SPs are associated with neonatal lung disease, respiratory distress syndrome (RDS or acute lung disease) or bronchopulmonary dysplasia (BPD or chronic lung disease). SPs play important roles in both normal lung function and innate host defense. Although maternal steroid therapy is widely used to avoid lung disease in infants born prematurely, not all fetal lungs respond and the long-term consequences are not fully understood. The general hypothesis under investigation states that multiple genetic factors contribute to the development of neonatal lung disease and RDS in particular. The goal in this application is to study regulatory mechanisms of human SPs shown to associate with neonatal lung disease (including RDS) and perform a genome-wide search of candidate genes for associations with RDS.
The Specific Aims i nclude the study of SP-A 5'UTR splice variants on translational regulation of human SP-A1 and SP-A2 by investigating trans- and cis- acting factors (Aim 1); the role of SP-B intron 4 variants on splicing by investigating the importance of sequence composition and size of intron, and by studying cis-acting elements (Aim 2); and genome-wide candidate genes associations with neonatal lung disease in a case (RDS)-control study by using a high throughput approach for genotyping tag single nucleotide polymorphisms (tag SNPs), as well as ancestry-informative SNP markers to quantitatively measure an individual's admixture estimate (IAE). A study of gene-gene and gene-environment interactions will be done by performing logistic regression analyses where SNP genotypes are used as independent variables and environmental factors (i.e. gestational age, weight, IAE, sex, maternal steroid treatment, and surfactant therapy) are included as covariates (Aim 3). The overall information obtained is likely to make significant contributions not only to the long-term objectives stated above, but also to lung diseases beyond neonatal lung disease. The physiologic importance of SPs in lung function and host defense places them at center stage for several lung diseases because most (if not all) of lung diseases are identified with derangements in either process. The significant findings from the genome-wide search of candidate genes will provide a solid foundation for future studies where evidence-based hypotheses can be investigated and may also provide insight (based on the location and characteristics of the SNPs that define the significant haplotypes) as to which of these genes contribute to RDS via a regulatory or functional derangement. ? ? ?
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