The long term goal of this project is to elucidate the developmental and hormonal regulation of the genes for surfactant phospholipid biosynthesis in late gestation fetal lung. The focus in the next funding period will be on glucocorticoid regulation of fatty-acid synthase (FAS). FAS is an important enzyme in surfactant synthesis as fatty acids are integral components of surfactant and they can also regulate synthesis of its major phospholipid, phosphatidylcholine. Although it has long been known that glucocorticoids accelerate surfactant production in the late gestation fetus and influence expression of the genes for surfactant proteins, FAS is so far the only gene for a lipogenic enzyme that has been shown to be under glucocorticoid regulation in fetal lung. It is proposed to determine how glucocorticoids enhance expression of the FAS gene and whether its expression is also enhanced by other hormones and agents that stimulate surfactant phospholipid synthesis.
Four Specific Aims are proposed to address these and related questions in fetal rat lung. l. Determine how dexamethasone (Dex) increases FAS mRNA levels. Determine if it increases mRNA stability, if the effects of Dex on mRNA content, stability and transcription in cultured lung explants are dependent on hormone concentration, gestational age and duration of culture, and if Dex increases FAS mRNA in vivo as it does in culture. 2. Determine if Dex increases FAS gene expression in fetal type II cells. 3. Identify hormone response domains and establish that there are nuclear proteins, in addition to the glucocorticoid receptor, involved in glucocorticoid regulation of FAS transcription. Binding assays and transient transfection assays will be used to identify regulatory DNA sequences. 4. Determine if other hormones and agents increase FAS activity and mRNA level and, if they do, how they interact with Dex. The focus will be on thyrotropin- releasing hormone, retinoic acid, vitamin D3 and cAMP. These studies are designed to elucidate the mechanism by which hormones increase the activity of a critical enzyme in surfactant production. Such information is essential to better design hormonal therapy for acceleration of fetal lung maturation and prevention of the respiratory distress syndrome and bronchopulmonary dysplasia, often consequences of lung immaturity and insufficient surfactant in premature newborn infants.
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|Roberts, Harold R; Escobar, Miguel; Monroe, Dougald M (2004) More information on patients with factor XI deficiency. Anesthesiology 101:1253-4|
|Gobran, Laurice I; Rooney, Seamus A (2004) Pulmonary surfactant secretion in briefly cultured mouse type II cells. Am J Physiol Lung Cell Mol Physiol 286:L331-6|
|Homer, Robert J; Zheng, Tao; Chupp, Geoff et al. (2002) Pulmonary type II cell hypertrophy and pulmonary lipoproteinosis are features of chronic IL-13 exposure. Am J Physiol Lung Cell Mol Physiol 283:L52-9|
|Beneke, S; Rooney, S A (2001) Glucocorticoids regulate expression of the fatty acid synthase gene in fetal rat type II cells. Biochim Biophys Acta 1534:56-63|
|Gobran, L I; Rooney, S A (2001) Regulation of SP-B and SP-C secretion in rat type II cells in primary culture. Am J Physiol Lung Cell Mol Physiol 281:L1413-9|
|Lu, Z; Gu, Y; Rooney, S A (2001) Transcriptional regulation of the lung fatty acid synthase gene by glucocorticoid, thyroid hormone and transforming growth factor-beta 1. Biochim Biophys Acta 1532:213-22|
|Rooney, S A (2001) Regulation of surfactant secretion. Comp Biochem Physiol A Mol Integr Physiol 129:233-43|
|Isohama, Y; Rooney, S A (2001) Glucocorticoid enhances the response of type II cells from newborn rats to surfactant secretagogues. Biochim Biophys Acta 1531:241-50|
|Hei, D J; Grass, J; Lin, L et al. (1999) Elimination of cytokine production in stored platelet concentrate aliquots by photochemical treatment with psoralen plus ultraviolet A light. Transfusion 39:239-48|
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