THE INFLUENCE OF BUTYRIC ACID ON SURFACTANT PROTEIN A GENE TRANSCRIPTION

这个项目关注的是发育中的肺对一种 内源性侮辱，丁酸。丁酸是已知的基因调控因子 表情。它的作用包括改变组蛋白乙酰化，DNA 甲基化和腺苷环化酶活性。丁酸水平升高 类似物，α-氨基丁酸，已在中国人的脐带血中被证实 糖尿病母亲(IDM)中的婴儿，他们的肺成熟延迟。 我们之前已经证明，在阿尔法培养胎鼠肺的外植体 氨基丁酸导致表面活性蛋白显著减少 A(SP-A)，而不是SP-B。这个项目的主要目标是 确定这种相互作用背后的机制。文化体系 将用于胎鼠肺和胎二型细胞的外植体 文化。 由于IDM提高了胰岛素水平，胰岛素和胰岛素的相互作用 丁酸对SP-A、B和C mRNA水平的影响将通过Northern分析进行检测 和原位杂交。丁酸盐效应的机制将是 在许多方面进行了探索。合成丁酸类似物的作用 它们通过特定的机制起作用，例如改变组蛋白乙酰化，或DNA 将进行甲基化检查。我们还将确定α-氨基丁酸 酸降低了胎肺中核组蛋白的乙酰化，以及它是否 通过减少SP-A基因的合成和/或增加SP-A基因的表达而发挥作用 退化。将使用蛋白质合成抑制剂来确定 这种代谢物的作用是否由蛋白质介导 转录调控因子。 在关于母亲糖尿病影响的研究中，大部分重点是 胰岛素和葡萄糖一直是研究的重点。我们的体外观察 提示丁酸代谢产物可能在抑制血管生成中起作用。 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细胞的作用机制 发育中的肺。

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.