THE INFLUENCE OF BUTYRIC ACID ON SURFACTANT PROTEIN A GENE TRANSCRIPTION

该项目的重点是肺的发展， 内源性损伤丁酸 丁酸是已知的基因调节剂 表情 它的作用包括改变组蛋白乙酰化，DNA 甲基化和腺苷酸环化酶活性。 丁酸含量升高 类似物，α-氨基丁酸，已被证明在脐带血， 糖尿病母亲（IDM）的婴儿，肺成熟延迟。 我们先前已经证明，在α细胞中培养胎鼠肺外植体， 氨基丁酸导致表面活性剂蛋白质的显著减少 A（SP-A），而非SP-B，mRNA。 该项目的主要目标是 确定这种相互作用的机制。 培养系统 将使用胎鼠肺和胎II型细胞的外植体 cultures. 由于IDM具有升高的胰岛素水平，因此胰岛素和 将通过北方分析检测丁酸盐对SP-A、B和C mRNA水平的影响 和原位杂交。 丁酸盐效应的机制将是 以多种方式探索。 合成丁酸类似物的作用 其通过特定机制起作用，例如改变组蛋白乙酰化，或DNA 将检测甲基化。 我们还将确定α-氨基丁酸 酸降低了胎肺中的核组蛋白乙酰化， 通过减少SP-A mRNA合成和/或增加SP-A mRNA 降解 蛋白质合成抑制剂将用于确定 这种代谢物的作用是否由蛋白质介导 转录调节因子。 在研究母亲糖尿病对婴儿的影响时， 胰岛素和葡萄糖的发展。 我们的体外观察 提示丁酸代谢物可能在抑制 肺成熟的重要组成部分，SP-A的出现。 这 该项目应进一步阐明丁酸盐对 肺发育

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.