Genetic Regulation of Surfactant Deficiency

Study Overview
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Brief Summary
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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
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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.

Official Title
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Genetic Regulation of Surfactant Deficiency in Human Newborn Infants

Conditions
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Respiratory Distress Syndrome, Newborn

Intervention / Treatment
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* Drug: Nutrient


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 6 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Genetic association<br>Infants with and without neonatal respiratory distress syndrome undergo surfactant gene sequencing to identify genomic variants associated with neonatal respiratory distress syndrome | |
| Nutrient<br>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<br>* 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.<br>* Other names: [1-13C1] acetate, [5,5,5-2H3] leucine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Association of specific variants or interactions among variants in SFTPB, SFTPC, and ABCA3 with neonatal respiratory distress syndrome | Statistical association of increased risk of neonatal respiratory distress in term or near term infants with specific genomic variants in SFTPB, SFTPC, and ABCA3 | 1 week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Statistical association of quantitative surfactant phospholipid metabolic characteristics with specific genomic variants in SFTPB, SFTPC, and ABCA3 | 1 week | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary surfactants, Pulmonary surfactant associated protein B, Pulmonary surfactant associated protein C, ATP-binding cassette protein sub member family A3