Respiratory disease remains a significant cause of morbidity and mortality in children. In order for the lungs to function properly, they need to produce pulmonary surfactant, a complex mixture of lipids and proteins that help keep the lungs inflated at the end of a breath. The underlying hypothesis of this proposal is that some types of lung disease that develop early in life have a genetic basis, specifically due to mutations in genes important for normal surfactant metabolism. The long-term goals are to identify basic causes of lung disease that will lead to improved diagnostic tests and therapies for lung disease. Previous work from this laboratory has demonstrated the significance of mutations in the genes encoding surfactant proteins B and C in neonatal lung disease and interstitial lung disease in older children.
The specific aims of the current proposal focus on the role of a third protein important in surfactant metabolism called ABCA3. The role of ABCA3 mutations in causing lung disease in newborn infants and older children will be examined by sequence analysis of the ABCA3 gene from three groups of patients with lung disease: premature and full-term infants with unusually severe lung disease for their gestational ages, older children and adults with different types of interstitial lung diseases, and patients and family members with mutations identified in the gene encoding surfactant protein C. The nature of the mutations in the ABCA3 protein will be correlated with the phenotype and the likely effects on ABCA3 protein expression. Finally for those patients in whom mutations in SP-B, SP-C, and ABCA3 mutations are not found, additional candidate genes for the cause of their lung disease will be examined. These studies will provide new insights into the causes of lung disease in children and adults, indicate genes that may be important in the pathogenesis of more common lung diseases, and enhance our understanding of aspects of normal surfactant metabolism. By improving our understanding of the specific causes of some types of lung diseases, this research will hopefully lead to better tests in order to be able to more easily diagnose certain kinds of lung disease and predict who is at risk for developing these kinds of lung disease. By understanding which genes are involved in causing lung disease and how changes in these genes cause the lung to not function correctly, this may lead to better treatments for some kinds of lung diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL054703-12
Application #
7618507
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Blaisdell, Carol J
Project Start
1995-09-01
Project End
2012-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
12
Fiscal Year
2009
Total Cost
$287,000
Indirect Cost
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Saddi, Vishal; Beggs, Sean; Bennetts, Bruce et al. (2017) Childhood interstitial lung diseases in immunocompetent children in Australia and New Zealand: a decade's experience. Orphanet J Rare Dis 12:133
Nevel, Rebekah J; Garnett, Errine T; Worrell, John A et al. (2016) Persistent Lung Disease in Adults with NKX2.1 Mutation and Familial Neuroendocrine Cell Hyperplasia of Infancy. Ann Am Thorac Soc 13:1299-304
Wambach, Jennifer A; Casey, Alicia M; Fishman, Martha P et al. (2014) Genotype-phenotype correlations for infants and children with ABCA3 deficiency. Am J Respir Crit Care Med 189:1538-43
Thavagnanam, Surendran; Cutz, Ernest; Manson, David et al. (2013) Variable clinical outcome of ABCA3 deficiency in two siblings. Pediatr Pulmonol 48:1035-8
Hamvas, Aaron; Deterding, Robin R; Wert, Susan E et al. (2013) Heterogeneous pulmonary phenotypes associated with mutations in the thyroid transcription factor gene NKX2-1. Chest 144:794-804
Henderson, Lindsay B; Melton, Kristin; Wert, Susan et al. (2013) Large ABCA3 and SFTPC deletions resulting in lung disease. Ann Am Thorac Soc 10:602-7
Gower, W Adam; Nogee, Lawrence M (2013) Candidate gene analysis of the surfactant protein D gene in pediatric diffuse lung disease. J Pediatr 163:1778-80
Young, Lisa R; Deutsch, Gail H; Bokulic, Ronald E et al. (2013) A mutation in TTF1/NKX2.1 is associated with familial neuroendocrine cell hyperplasia of infancy. Chest 144:1199-1206
Flamein, Florence; Riffault, Laure; Muselet-Charlier, CĂ©line et al. (2012) Molecular and cellular characteristics of ABCA3 mutations associated with diffuse parenchymal lung diseases in children. Hum Mol Genet 21:765-75
Wambach, Jennifer A; Wegner, Daniel J; Depass, Kelcey et al. (2012) Single ABCA3 mutations increase risk for neonatal respiratory distress syndrome. Pediatrics 130:e1575-82

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