Genetic regulation of neonatal pulmonary surfactant deficiency has been suggested by studies of gender, genetic linkage, recurrent familial cases, gene knockout models in mice, and by racial disparity in risk of neonatal respiratory distress syndrome (RDS). Successful fetal-neonatal pulmonary transition requires production of the pulmonary surfactant, a phospholipid-protein film that lines alveoli and maintains alveolar patency at end expiration. Our goals are to understand the genetic mechanisms that disrupt pulmonary surfactant metabolism and cause neonatal respiratory distress syndrome as well as to understand the implications of these genetic mechanisms on the development of interstitial lung disease and pulmonary fibrosis.
To understand these genetic mechanisms, we are investigating the association of genetic variation in several genes where mutations cause lethal surfactant deficiency (SFTPB, SFTPC, ABCA3, and the thyroid transcription factor gene, NKX2-1), as well as other genes involved in pulmonary surfactant synthesis, transport, and catabolism, the unfolded protein response, and fluid homeostasis, to RDS.
We employ Sanger and next generation sequencing and gene expression arrays to identify variants in candidate genes, and cell culture/transfection systems to test the functionality of these variants.
Improved understanding of genetic regulation of surfactant deficiency will suggest novel diagnostic strategies that identify and categorize high risk infants and therapeutic strategies that target discrete steps in pulmonary surfactant metabolism to improve outcomes of infants with neonatal respiratory distress syndrome.
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