Genetic Regulation of Surfactant Deficiency
Condition: Respiratory Distress Syndrome, Newborn
MeSH terms: Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn
Study type: Observational

Summary: 
      Inherited deficiencies in any one of 3 genes (surfactant protein B, surfactant protein C, and
      ATP-binding cassette transporter A3) can cause neonatal respiratory distress syndrome by
      disrupting metabolism of the pulmonary surfactant. The investigators will use state of the
      art methods to link specific changes in the genetic code of each of these genes with
      disruption of discrete steps in the metabolism of the pulmonary surfactant in human newborn
      infants. These studies will lead to improved diagnostic capabilities and suggest novel
      strategies to correct surfactant deficiency in newborn infants.
    

Detailed description: 
      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.
    

Intervention name(s): Nutrient
Intervention type(s): Drug
Intervention description(s): We administer stable isotopically labeled precursors of surfactant phospholipids ([1-13C1] acetate) and of surfactant protein-B ([5,5,5-2H3] leucine) to infants with neonatal respiratory distress syndrome. Using mass spectrometry, we measure incorporation of stable isotopically labeled precursors in tracheal aspirates and compare surfactant phospholipid and surfactant protein-B turnover.
Other intervention name(s): [1-13C1] acetate, [5,5,5-2H3] leucine
Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        The study population includes infants with and without neonatal respiratory distress
        syndrome (N=513) and infants with varying severity of neonatal respiratory distress
        syndrome (N=12).
      
Biospecimen description: 
      DNA samples and tracheal aspirate samples
    
Keywords: Pulmonary surfactants; Pulmonary surfactant associated protein B; Pulmonary surfactant associated protein C; ATP-binding cassette protein sub member family A3