MOLECULAR BIOLOGY OF GROWTH REGULATION BY NUTRITION

描述（改编自申请人摘要）：具体变更 在IGF-I、IGF-II和白蛋白基因表达中， 由于营养不足而停止生长。 的至少一部分 mRNA的减少是转录后的。 营养研究 白蛋白合成的调节将包括分析 氨基酸限制对白蛋白mRNA稳定性的影响。 其他实验将 包括克隆全长白蛋白cDNA的定点诱变， 检验导致白蛋白mRNA减少的缺陷 在氨基酸限制性细胞中的丰度， 白蛋白mRNA。 此外，白蛋白基因表达的调节， 将在Nagase研究完整动物中的蛋白质限制 在表达白蛋白小基因的转基因小鼠中 或白蛋白小基因的突变构建体。 营养研究 IGF-II合成的调节将包括分析 IGF-II mRNA稳定性的氨基酸限制，以及IGF-II mRNA的鉴定。 IGF-II mRNA的3 '-非翻译区中的序列，其涉及 通过氨基酸可用性进行调节。 IGF的正常途径- II mRNA降解将与氨基转移酶中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 mRNA表达的影响 丰度和基因转录将在培养大鼠中进行研究 肝细胞 将确定长3 '- IGF-I mRNA的8 kb非翻译区参与了其表达。 在氨基酸限制性培养细胞中的调节。

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.