Genetic Regulation of Surfactant Deficiency

Genetic regulation of neonatal pulmonary surfactant deficiency has been suggested by studies
of gender, genetic linkage, recurrent familial cases, targeted gene ablation in murine
lineages, and by racial disparity in risk of neonatal respiratory distress syndrome.
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 goal is to understand the genetic mechanisms that disrupt pulmonary
surfactant metabolism and cause neonatal respiratory distress syndrome. Studies in human
newborn infants have demonstrated that 3 genes are critical for surfactant metabolism:
surfactant protein B (SFTPB), surfactant protein C (SFTPC), and an ATP-binding cassette
transporter, ABCA3 (ABCA3). To understand genetic regulatory mechanisms, we will investigate
the contribution of variation in each of these genes to risk of neonatal respiratory distress
syndrome by testing the hypothesis that genetic variants in the SFTPB, SFTPC, and ABCA3
disrupt pulmonary surfactant metabolism. Using high throughput automated sequencing to
genotype, multidimensional protein identification technology to assess quantitative and
qualitative differences in surfactant protein B and C expression, in vivo metabolic labeling
with stable isotopically labeled precursors to estimate surfactant protein B and C and
phospholipid metabolic rates, and cohort sizes that provide statistical power (0.8), we will
use race-specific, severity-stratified case-control (N=480) and case comparison (N=250)
designs to understand genetically regulated, metabolic mechanisms that cause surfactant
deficiency by disrupting expression or altering processing of surfactant proteins B or C or
by disrupting surfactant phospholipid composition in human newborn infants. Improved
understanding of genetic regulation of surfactant deficiency will suggest novel diagnostic
strategies to 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.

Inclusion Criteria:

- Infants who require mechanical ventilation via endotracheal tube or tracheostomy in
the first year of life

Exclusion Criteria:

- Infants with conditions likely to cause imminent death