The hypothesis is that delayed lung development in the fetus of the diabetic woman is related to surfactant-associated protein deficiency caused by high levels of insulin.
Aim 1 is to elucidate the signal transduction pathways involved in insulin-mediated inhibition of SP-A and SP-B gene expression. Signal transduction inhibitors, enzyme assays, characterization of signaling intermediates and transfection with dominant negative and constitutively active constructs will be used to test the hypothesis that the PI-3K signal transduction pathway mediates the effects of insulin.
Aim 2 is to identify the cis-acting elements in the SP-A and SP-B genes which mediate the inhibitory effects of insulin. Luciferase reporter gene constructs will be used to localize inhibitory insulin response elements in the 5' flanking region of the human SP-A1 and SP-A2 genes.
Aim 3 is to identify the transcription factors that interact with the SP-A1 and SP-B insulin response elements. Electrophoretic mobility shift assays will be used to test the hypothesis that HNF-3a and C/EBPa mediate the insulin-induced inhibition of SP-A and SP-B gene expression.
Aim 4 is to describe the molecular events (phosphorylation, localization, and/or changes in gene expression) that link signal transduction to transcription factors which interact with the insulin response elements in the SP-A1 and SP-B genes.
|Fischer, Anthony J; Goss, Kelli L; Scheetz, Todd E et al. (2009) Differential gene expression in human conducting airway surface epithelia and submucosal glands. Am J Respir Cell Mol Biol 40:189-99|
|Snyder, Gary D; Oberley-Deegan, Rebecca E; Goss, Kelli L et al. (2008) Surfactant protein D is expressed and modulates inflammatory responses in human coronary artery smooth muscle cells. Am J Physiol Heart Circ Physiol 294:H2053-9|
|Oberley, Rebecca E; Goss, Kelli L; Hoffmann, Darren S et al. (2007) Regulation of surfactant protein D in the mouse female reproductive tract in vivo. Mol Hum Reprod 13:863-8|
|Oberley, Rebecca E; Goss, Kelli L; Quintar, Amado A et al. (2007) Regulation of surfactant protein D in the rodent prostate. Reprod Biol Endocrinol 5:42|
|Garbrecht, Mark R; Klein, Jonathan M; McCarthy, Troy A et al. (2007) 11-Beta hydroxysteroid dehydrogenase type 2 in human adult and fetal lung and its regulation by sex steroids. Pediatr Res 62:26-31|
|Garbrecht, Mark R; Schmidt, Thomas J; Krozowski, Zygmunt S et al. (2006) 11Beta-hydroxysteroid dehydrogenase type 2 and the regulation of surfactant protein A by dexamethasone metabolites. Am J Physiol Endocrinol Metab 290:E653-60|
|Garbrecht, Mark R; Krozowski, Zygmunt S; Snyder, Jeanne M et al. (2006) Reduction of glucocorticoid receptor ligand binding by the 11-beta hydroxysteroid dehydrogenase type 2 inhibitor, Thiram. Steroids 71:895-901|
|Garbrecht, Mark R; Klein, Jonathan M; Schmidt, Thomas J et al. (2006) Glucocorticoid metabolism in the human fetal lung: implications for lung development and the pulmonary surfactant system. Biol Neonate 89:109-19|
|George, Caroline L S; White, Misty L; Kulhankova, Katarina et al. (2006) Early exposure to a nonhygienic environment alters pulmonary immunity and allergic responses. Am J Physiol Lung Cell Mol Physiol 291:L512-22|
|Oberley, Rebecca E; Goss, Kelli L; Dahmoush, Laila et al. (2005) A role for surfactant protein D in innate immunity of the human prostate. Prostate 65:241-51|
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