This project focuses on the response of the developing lung to an endogenous insult, butyric acid. Butyric acid is known regulator of gene expression. Its actions include altering histone acetylation, DNA methylation and adenyl cyclase activity. Elevated levels of a butyric acid analog, alpha aminobutyric acid, have been demonstrated in cord blood of infants in diabetic mothers (IDM), who have delayed lung maturation. We have previously shown that culturing explants of fetal rat lung in alpha aminobutyric acid results in a significant reduction in surfactant protein A (SP-A), but not SP-B, mRNA. The primary goal of this project is to identify the mechanisms underlying this interaction. The culture systems to be used will be explants of fetal rat lung and fetal type II cell cultures. Since IDM have elevated insulin levels, the interaction of insulin and butyrate on SP-A, B and C mRNA levels will be examined by Northern analysis and in situ hybridization. The mechanism of the butyrate effect will be explored in a number of ways. The effects of synthetic butyrate analogs which act via specific mechanisms eg altering histone acetylation, or DNA methylation will be examined. We will also determine if alpha aminobutyric acid decreases nuclear histone acetylation in the fetal lung and whether it acts by decreasing SP-A mRNA synthesis and/or increasing SP-A mRNA degradation. Protein synthesis inhibitors will be used to ascertain whether the action of this metabolite is mediated by protein transcriptional regulators. Much of the emphasis in studies of the impact of maternal diabetes on development has been on insulin and glucose. Our in vitro observations suggest that butyric acid metabolites may play a role in inhibiting an important component of lung maturation, the appearance of SP-A. This project should further elucidate the mechanism of butyrate action on the developing lung.
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