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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Respiratory Integrative Biology and Translational Research Study Section (RIBT)
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Blaisdell, Carol J
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Johns Hopkins University
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