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Fetal-Glycogen Regulation by Insulin-like Growth Factors

胰岛素样生长因子对胎儿糖原的调节

基本信息

批准号：
7529166
负责人：
MARY FRANCES LOPEZ
金额：
$ 11.2万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-30 至 2009-03-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7529166
关键词：
Adult Affinity Binding Binding Proteins Biological Birth Blood Glucose Cell Surface Receptors Data Family Fetal Liver Fetus Genes Genetic Glucose Glycogen Glycogen (Starch) Synthase Goals Growth Hepatic Hepatocyte Homeostasis Hormonal Hormones IGF Type 2 Receptor In Vitro Insulin Insulin Receptor Insulin-Like Growth Factor I Insulin-Like Growth Factor Receptor Insulin-Like-Growth Factor I Receptor Knock-out Laboratories Lead Life Ligands Liver Liver Glycogen Mediating Mothers Mus Newborn Infant Numbers Pancreas Pancreatic Hormones Phosphatidylinositols Phosphorylation Phosphotransferases Play Pregnancy Process Production Proteins Proto-Oncogene Proteins c-akt Regulation Role Serine Serum Signal Pathway Somatomedins System Threonine Tissues Wild Type Mouse analog carbohydrate metabolism critical developmental period fetal glucose metabolism glucose uptake glycogen metabolism glycogenesis hormone regulation insight liver function mouse model peptide hormone postnatal receptor repository research study response transcription factor

项目摘要

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.

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，糖原的一种形式，可以根据需要动员。胰岛素是一种胰腺激素，在维持葡萄糖代谢正常稳态中的重要作用。在成人肝脏中，胰岛素可以引发包括葡萄糖摄取和糖原合成在内的多种生物反应。但不目前还不清楚胰岛素或其他激素是否在调节胎儿糖原合成中起类似的作用。我的实验室提供的证据表明，缺乏转录因子PDX-1的小鼠（胰腺和十二指肠同源框基因-1），胰岛素缺乏，在他们的肝脏中没有任何改变，糖原在产前储存，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，在整个胎儿期高度表达。缺乏IGF-II的小鼠不仅出生时生长迟缓，而且肝糖原显著降低在妊娠晚期，其储存量高于其野生型（WT）同窝仔。假设IGF-II是胎儿肝脏糖原合成的主要激素调节剂，通过胰岛素受体介导这种效应。这个提议的目的是逐步剖析这个过程胎儿肝脏碳水化合物代谢，从通过细胞表面受体的激素调节，细胞内信号通路。该实验方法将利用不同的小鼠，可能在糖原合成的胎儿调节中起作用的蛋白质的缺失（敲除）。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）确定哪种受体调节胎肝糖原合成;和3）阐明细胞内调节胎儿糖原合成的信号通路。这些实验的数据将提供使我们更好地了解IGF-II和胰岛素的共同功能，并可能导致深入了解胰岛素作用。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Decreased motoneuron survival in Igf2 null mice after sciatic nerve transection.

坐骨神经横断后 Igf2 缺失小鼠的运动神经元存活率降低。

DOI：
10.1097/wnr.0b013e328330b735
发表时间：
2009
期刊：
Neuroreport
影响因子：
1.7
作者：
Silva,Delia;Dikkes,Pieter;Barnes,Medina;Lopez,MaryFrances
通讯作者：
Lopez,MaryFrances

Placental glycogen stores are increased in mice with H19 null mutations but not in those with insulin or IGF type 1 receptor mutations.

DOI：
10.1016/j.placenta.2009.05.004
发表时间：
2009-08
期刊：
Placenta
影响因子：
3.8
作者：
Esquiliano DR;Guo W;Liang L;Dikkes P;Lopez MF
通讯作者：
Lopez MF

Insulin-like growth factor 2 and the insulin receptor, but not insulin, regulate fetal hepatic glycogen synthesis.

胰岛素样生长因子 2 和胰岛素受体（但不是胰岛素）调节胎儿肝糖原的合成。

DOI：
10.1210/en.2009-0705
发表时间：
2010
期刊：
Endocrinology
影响因子：
4.8
作者：
Liang,Li;Guo,WeiHui;Esquiliano,DiegoR;Asai,Masato;Rodriguez,Susana;Giraud,Jodel;Kushner,JakeA;White,MorrisF;Lopez,MaryFrances
通讯作者：
Lopez,MaryFrances