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Genetic Regulation of Surfactant Deficiency

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ClinicalTrials.gov Identifier: NCT00828243
Recruitment Status : Completed
First Posted : January 23, 2009
Last Update Posted : October 21, 2014
Information provided by (Responsible Party):

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
Respiratory Distress Syndrome, Newborn Drug: Nutrient

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

Study Type : Observational
Actual Enrollment : 773 participants
Observational Model: Case Control
Time Perspective: Prospective
Official Title: Genetic Regulation of Surfactant Deficiency in Human Newborn Infants
Study Start Date : November 2007
Primary Completion Date : March 2013
Study Completion Date : March 2013

Groups and Cohorts

Group/Cohort Intervention/treatment
Infants with varying degrees of neonatal respiratory distress syndrome
Infants up to 6 months of age with varying severity of respiratory distress receive stable isotopically labeled nutrients (precursors of surfactant phospholipids or proteins) to permit mass spectrometry-based measurement of surfactant kinetics.
Drug: Nutrient
We administer stable isotopically labeled precursors of surfactant phospholipids (palmitate and acetate) and of surfactant-associated proteins (leucine) to infants with neonatal respiratory distress syndrome. We measure with mass spectrometry incorporation of stable isotopically labeled precursors into tracheal aspirates to estimate surfactant phospholipid and protein kinetics.
Other Name: Palmitate, acetate, leucine

Outcome Measures

Primary Outcome Measures :
  1. Association of specific variants or interactions among variants in SFTPB, SFTPC, and ABCA3 with neonatal respiratory distress syndrome [ Time Frame: 1 week ]

Secondary Outcome Measures :
  1. 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 [ Time Frame: 1 week ]

Biospecimen Retention:   Samples With DNA
DNA samples and tracheal aspirate samples will be retained on each study participant.

Eligibility Criteria

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Ages Eligible for Study:   up to 1 Year   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
The study population includes infants with and without neonatal respiratory distress syndrome (N=480) and infants with varying severity of neonatal respiratory distress syndrome (N=250).

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
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00828243

United States, Missouri
St. Louis Children's Hospital
St. Louis, Missouri, United States, 63110
Sponsors and Collaborators
Washington University School of Medicine
National Heart, Lung, and Blood Institute (NHLBI)
Principal Investigator: F. S. Cole, M.D. Washington University School of Medicine
More Information


Responsible Party: F. Sessions Cole, MD, Professor of Pediatrics, Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT00828243     History of Changes
Other Study ID Numbers: 07-0156
R01HL082747 ( U.S. NIH Grant/Contract )
First Posted: January 23, 2009    Key Record Dates
Last Update Posted: October 21, 2014
Last Verified: October 2014

Keywords provided by F. Sessions Cole, MD, Washington University School of Medicine:
Pulmonary surfactants
Pulmonary surfactant associated protein B
Pulmonary surfactant associated protein C
ATP-binding cassette protein sub member family A3

Additional relevant MeSH terms:
Respiratory Distress Syndrome, Newborn
Respiratory Distress Syndrome, Adult
Lung Diseases
Respiratory Tract Diseases
Respiration Disorders
Infant, Premature, Diseases
Infant, Newborn, Diseases
Pulmonary Surfactants
Pulmonary Surfactant-Associated Proteins
Pulmonary Surfactant-Associated Protein B
Pulmonary Surfactant-Associated Protein C
Respiratory System Agents