Genetic Regulation of Surfactant Deficiency
Study Details
Study Description
Brief 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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Genetic association Infants with and without neonatal respiratory distress syndrome undergo surfactant gene sequencing to identify genomic variants associated with neonatal respiratory distress syndrome |
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| Nutrient To newborn infants with respiratory distress syndrome, we administer stable isotopically labeled nutrients (precursors of surfactant phospholipids or proteins) to permit mass spectrometry-based comparison of surfactant phospholipid and protein turnover. |
Drug: Nutrient
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 Names:
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Outcome Measures
Primary Outcome Measures
- Association of specific variants or interactions among variants in SFTPB, SFTPC, and ABCA3 with neonatal respiratory distress syndrome [1 week]
Statistical association of increased risk of neonatal respiratory distress in term or near term infants with specific genomic variants in SFTPB, SFTPC, and ABCA3
Secondary Outcome Measures
- Association of specific variants or interactions among variants in SFTPB, SFTPC, and ABCA3 with fractional synthetic rate and/or fractional catabolic rate of surfactant phospholipids, surfactant protein-B, and surfactant protein-C [1 week]
Statistical association of quantitative surfactant phospholipid metabolic characteristics with specific genomic variants in SFTPB, SFTPC, and ABCA3
Eligibility Criteria
Criteria
Inclusion Criteria:
- Newborn infants with respiratory distress syndrome who require mechanical ventilation via endotracheal tube or tracheostomy in the first 6 months of life
Exclusion Criteria:
- Infants with conditions likely to cause imminent death
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | St. Louis Children's Hospital | Saint Louis | Missouri | United States | 63110 |
Sponsors and Collaborators
- Washington University School of Medicine
- National Heart, Lung, and Blood Institute (NHLBI)
Investigators
- Principal Investigator: F. S. Cole, M.D., Washington University School of Medicine
Study Documents (Full-Text)
None provided.More Information
Publications
- Hamvas A, Heins HB, Guttentag SH, Wegner DJ, Trusgnich MA, Bennet KW, Yang P, Carlson CS, An P, Cole FS. Developmental and genetic regulation of human surfactant protein B in vivo. Neonatology. 2009;95(2):117-24. doi: 10.1159/000153095. Epub 2008 Sep 6.
- Tomazela DM, Patterson BW, Hanson E, Spence KL, Kanion TB, Salinger DH, Vicini P, Barret H, Heins HB, Cole FS, Hamvas A, MacCoss MJ. Measurement of human surfactant protein-B turnover in vivo from tracheal aspirates using targeted proteomics. Anal Chem. 2010 Mar 15;82(6):2561-7. doi: 10.1021/ac1001433.
- 07-0156
- R01HL082747