MOLECULAR BIOLOGY OF GROWTH REGULATION BY NUTRITION

描述(改编自申请人的摘要)：具体修改 在IGF-I、IGF-II和白蛋白基因表达中，观察到 由于营养不足而导致生长受阻。至少部分 MRNA的减少是转录后的。营养学研究 白蛋白合成的调节将包括对以下因素的影响的分析 氨基酸限制对白蛋白mRNA稳定性的影响。其他实验将会 涉及克隆的全长白蛋白基因的定点突变，以 检验缺陷导致白蛋白mRNA减少的假设 翻译受损的氨基酸限制性细胞中的丰度 白蛋白基因。此外，白蛋白基因表达的调节通过 完整动物的蛋白质限制将在NAGase中进行研究 白蛋白缺乏症大鼠和表达白蛋白微型基因的转基因小鼠 或白蛋白微型基因的突变结构。营养学的研究 对IGF-II合成的调控将包括分析 氨基酸对胰岛素样生长因子-II基因稳定性的限制及鉴定 涉及IGF-II基因3‘非翻译区的序列 通过氨基酸的可获得性进行调节。胰岛素样生长因子的正常途径- II信使核糖核酸的降解将与氨基利用的途径进行比较。 酸限制细胞。氨基酸限制对胰岛素样生长因子-I基因表达的影响 将在培养的大鼠中研究丰度和基因转录 肝细胞。将确定长3‘中的序列是否- 8kb的IGF-I基因的非翻译区参与了其 氨基酸限制培养细胞的调控。

DESCRIPTION (adapted from the applicant's abstract): Specific alterations in IGF-I, IGF-II and albumin gene expression are observed in animals that are growth-arrested due to nutritional insufficiency. At least part of the reduction in mRNA is post-transcriptional. Studies of nutritional regulation of albumin synthesis will include an analysis of the effect of amino acid restriction on albumin mRNA stability. Other experiments will involve site-directed mutagenesis of a cloned full-length albumin cDNA, to test the hypothesis that the defect leading to decreased albumin mRNA abundance in amino acid-restricted cells in impaired translation of albumin mRNA. Additionally, regulation of albumin gene expression by protein restriction in intact animals will be studied in Nagase analbuminemic rats and in transgenic mice expressing an albumin minigene or mutant constructs of the albumin minigene. Studies of the nutritional regulation of IGF-II synthesis will include analysis of the effects of amino acid restriction of IGF-II mRNA stability, and identification of sequences in the 3'-untranslated region of IGF-II mRNA which are involved in its regulation by amino acid availability. The normal pathway for IGF- II mRNA degradation will be compared with the pathway utilized in amino acid-restricted cells. The effect of amino acid restriction of IGF-I mRNA abundance and gene transcription will be studied in cultured rat hepatocytes. It will be determined if sequences in the long 3'- untranslated region of the 8 kb species of IGF-I mRNA are involved in its regulation in amino acid-restricted cultured cells.