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: 6804705
• 负责人: MARY FRANCES LOPEZ
• 金额: $ 24.38万
• 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/6804705
• 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（申请人提供）：肝脏的主要功能之一是维持血糖水平。它是葡萄糖的储存库，以糖原的形式，可以根据需要进行动员。胰岛素是一种胰腺激素，在维持葡萄糖代谢的正常稳态中起重要作用。在成人肝脏中，胰岛素可以触发多种生物反应，包括葡萄糖摄取和糖原合成。然而，目前尚不清楚胰岛素或其他激素是否在调节胎儿糖原合成方面发挥类似作用。我的实验室提供的证据表明，胰岛素缺乏的小鼠缺乏转录因子PDX-1（胰腺和十二指肠同源盒基因-1），在产前肝糖原储存没有任何改变，这表明胰岛素可能不是出生前糖原合成所必需的。胰岛素样生长因子- ii （IGF-II）可能是调节胎儿糖原合成的一个候选因子。IGF-II是一种肽类激素，属于胰岛素家族，在整个胎儿期都高度表达。缺乏IGF-II的小鼠不仅出生时生长迟缓，而且在妊娠后期的肝糖原储存也明显低于野生型（WT）小鼠。假设IGF-II是胎儿肝脏中糖原合成的主要激素调节剂，它通过胰岛素受体介导这种作用。本研究的目的是逐步剖析胎儿肝脏碳水化合物代谢的过程，从细胞表面受体的激素调节到细胞内信号通路。实验方法将利用基因缺失（敲除）蛋白质的不同小鼠，这些蛋白质可能在胎儿调节糖原合成中发挥作用。我们的目的是：1)确认IGF-II是在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通路。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，并可能导致对胰岛素作用的深入了解。