Fetal-Glycogen Regulation by Insulin-like Growth Factors

胰岛素样生长因子对胎儿糖原的调节

• 批准号: 6950664
• 负责人: MARY FRANCES LOPEZ
• 金额: $ 5.32万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2006-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6950664
• 关键词: biological signal transduction; carbohydrate metabolism; embryo /fetus; embryo /fetus tissue /cell culture; gene deletion mutation; gene targeting; glycogen; glycogenesis; hormone regulation /control mechanism; insulin receptor; insulinlike growth factor; intracellular transport; laboratory mouse; liver cells; liver metabolism

DESCRIPTION (provided by applicant): One of the main functions of the liver is to maintain blood glucose levels. It is a repository of glucose in the form of glycogen that can be mobilized upon demand. Insulin is a pancreatic hormone that plays an important role in maintaining normal homeostasis of glucose metabolism. In the adult liver, insulin can trigger a variety of biological responses including glucose uptake and glycogen synthesis. However, it is not clear whether insulin or other hormones play a similar in the regulation of glycogen synthesis in the fetus. My laboratory has provided evidence that mice lacking the transcription factor PDX-1 (pancreatic and duodenal homoeobox gene-1), which are insulin deficient, do not have any alterations in their hepatic glycogen stores prenatally, suggesting that insulin may not be essential for glycogen synthesis before birth. A likely candidate for the regulation of glycogen synthesis in the fetus is insulin-like growth factor-II (IGF-II). IGF-II is a peptide hormone that belongs to the insulin family that is highly expressed throughout fetal life. Mice deficient in IGF-II are not only born growth-retarded but also have significantly lower hepatic glycogen stores than their wild-type (WT) littermates during late gestation. The hypothesis is that IGF-II is the main hormonal regulator of glycogen synthesis in the fetal liver and that it mediates this effect via the insulin receptor. The goal of this proposal is to dissect step by step the process of hepatic carbohydrate metabolism in the fetus, from hormonal regulation via cell surface receptors to intracellular signaling pathways. The experimental approach will make use of different mice with genetic deletions (knockouts) of proteins that may play a role in the fetal regulation of glycogen synthesis. Our aims are: 1) To confirm that IGF-II is the hormonal ligand involved in hepatic glycogen synthesis before birth; 2) To determine which receptor(s) regulates fetal hepatic glycogen synthesis; and 3) To elucidate the intracellular signaling pathways that regulate glycogen synthesis in the fetus. Data from these experiments will provide us with a better understanding of the common functions of IGF-II and insulin and may lead to insights into insulin action.

描述（由申请人提供）：肝脏的主要功能之一是维持血糖水平。它是以糖原形式存在的葡萄糖储存库，可以根据需要调动。胰岛素是一种胰腺激素，在维持葡萄糖代谢的正常稳态中发挥着重要作用。在成人肝脏中，胰岛素可以引发多种生物反应，包括葡萄糖摄取和糖原合成。然而，尚不清楚胰岛素或其他激素是否在胎儿糖原合成的调节中发挥类似作用。 我的实验室提供的证据表明，缺乏转录因子 PDX-1（胰腺和十二指肠同源框基因-1）的小鼠（即胰岛素缺乏）在产前的肝糖原储存中没有任何变化，这表明胰岛素对于出生前的糖原合成可能不是必需的。 调节胎儿糖原合成的可能候选者是胰岛素样生长因子-II (IGF-II)。 IGF-II 是一种肽激素，属于胰岛素家族，在整个胎儿生命中高度表达。 缺乏 IGF-II 的小鼠不仅出生时生长迟缓，而且在妊娠后期其肝糖原储备显着低于野生型 (WT) 同窝小鼠。 假设认为 IGF-II 是胎儿肝脏中糖原合成的主要激素调节剂，并且它通过胰岛素受体介导这种作用。该提案的目标是逐步剖析胎儿肝脏碳水化合物代谢的过程，从通过细胞表面受体的激素调节到细胞内信号传导途径。该实验方法将利用具有蛋白质基因缺失（敲除）的不同小鼠，这些蛋白质可能在胎儿糖原合成的调节中发挥作用。我们的目标是：1）确认IGF-II是出生前参与肝糖原合成的激素配体； 2) 确定哪些受体调节胎儿肝糖原合成； 3) 阐明调节胎儿糖原合成的细胞内信号传导途径。这些实验的数据将使我们更好地了解 IGF-II 和胰岛素的共同功能，并可能深入了解胰岛素的作用。