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TISSUE SPECIFIC REGULATION OF GLUCOSE METABOLISM AND INSULIN ACTION IN IUGR FETUS

IUGR 胎儿葡萄糖代谢和胰岛素作用的组织特异性调节

基本信息

批准号：
8720530
负责人：
Stephanie R Wesolowski
金额：
$ 14.18万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8720530
关键词：
Adult Age Animal Organ Biological Assay Birth Career Choice Catheters Citric Acid Cycle DNA Methylation Data Development Elderly Epigenetic Process Evolution Faculty Fetal Growth Retardation Fetal Liver Fetal Tissues Fetal Weight Fetus Gene Expression Gene Expression Regulation Gene Proteins Gene Targeting Gluconeogenesis Glucose Glycolysis Goals Growth Health Hepatic Hepatocyte Hindlimb Hyperinsulinism Insulin Insulin Resistance K-Series Research Career Programs Laboratories Life Link Liver Liver Extract Measurement Measures Mediating Mentors Metabolic Metabolic Diseases Metabolism Methodology Methods Modeling Molecular Muscle Nuclear Nutrient Operative Surgical Procedures Organ Oxygen Peripheral Phenotype Phosphoenolpyruvate Carboxylase Physiology Post-Translational Protein Processing Predisposition Pregnancy Preparation Regulation Role Saline Sampling Sheep Signal Pathway Signaling Protein Skeletal Muscle Techniques Testing Tissue Sample Tissues Tracer Training Transcriptional Regulation basal insulin base cofactor critical period detection of nutrient fetal fetal programming glucose metabolism glucose production glucose uptake histone modification insulin sensitivity metabolomics novel offspring oxidation postnatal prevent programs response skills uptake

项目摘要

DESCRIPTION (provided by applicant): My long-term goal is to understand how altered nutrient supply programs fetal metabolism and how these changes may persist after birth and increase susceptibility to adult metabolic disease. Decreased or increased nutrient supply during critical periods in fetal life can have a major impact on the development and function of tissues and organs which may have a permanent effect on nutrient sensing and increase susceptibility to metabolic disease in adult life. Our recent data demonstrate that glucose production and gluconeogenic gene expression, which are normally absent during fetal life, are strikingly up-regulated in the late gestation IUGR fetal sheep. Our data also indicate that insulin fails to suppress glucose production in the IUGR fetus, yet robustly increases whole body rates of glucose utilization and oxidation, suggesting that the IUGR fetus develops liver-specific insulin resistance but increased peripheral insulin action. This career development award will use integrative approaches in fetal physiology and metabolism combined with novel metabolomic, molecular, and epigenetic techniques to test the hypothesis that the IUGR fetus develops tissue specific adaptations in insulin sensitivity and metabolism necessary for survival at the expense of somatic growth. Specifically, I will acquire surgical skills for fetal hepatic and hindlimb catheter preparations and develop new tracer methodologies for measurement of glucose and lactate metabolism in the whole fetus and across specific tissues including the liver and hindlimb, representing skeletal muscle as its metabolically active component. I will develop NMR metabolomics techniques to measure tissue metabolites, including intermediates, cofactors, and substrates for glycolysis, gluconeogenesis, and the TCA cycle. At the molecular level, I will gain expertise in assays of nuclear function, gene regulation, and epigenetics to determine mechanisms for differential insulin sensitivity in liver and skeletal muscle. The core laboratories, faculty mentoring, and training plan outlined in this proposal will allow me to develop advanced training in the execution of these methods that are essential steps in the evolution of my career path aimed at understanding the mechanisms for fetal metabolic programming at the level of the whole animal, organ/tissue, and molecular level. These studies will provide novel information regarding glucose and lactate metabolism and insulin action in the IUGR fetus and the coordination of metabolism between the fetal liver and skeletal muscle. These studies will also generate important concepts about the early development of signaling proteins and pathways linking IUGR to increased glucose production and insulin resistance in the liver and mechanisms that promote glucose uptake and utilization in skeletal muscle.

描述（由申请人提供）：我的长期目标是了解营养供应的改变如何影响胎儿代谢，以及这些变化如何在出生后持续存在并增加对成人代谢疾病的易感性。胎儿生命关键时期营养供应的减少或增加会对组织和器官的发育和功能产生重大影响，这可能对营养感知产生永久性影响，并增加成年后对代谢疾病的易感性。我们最近的数据表明，胎儿时期通常不存在的葡萄糖产生和糖异生基因表达在妊娠晚期 IUGR 胎羊中显着上调。我们的数据还表明，胰岛素无法抑制 IUGR 胎儿的葡萄糖产生，但会大幅增加全身葡萄糖利用和氧化的速率，这表明 IUGR 胎儿会出现肝脏特异性胰岛素抵抗，但外周胰岛素作用增加。该职业发展奖将利用胎儿生理学和新陈代谢的综合方法，结合新颖的代谢组学、分子和表观遗传学技术来检验以下假设：IUGR 胎儿以牺牲体细胞生长为代价，在胰岛素敏感性和代谢方面发展出生存所需的组织特异性适应。具体来说，我将获得胎儿肝脏和后肢导管准备的外科技能，并开发新的示踪剂方法，用于测量整个胎儿以及包括肝脏和后肢在内的特定组织的葡萄糖和乳酸代谢，代表骨骼肌作为其代谢活性成分。我将开发 NMR 代谢组学技术来测量组织代谢物，包括糖酵解、糖异生和 TCA 循环的中间体、辅因子和底物。在分子水平上，我将获得核功能、基因调控和表观遗传学分析方面的专业知识，以确定肝脏和骨骼肌中胰岛素敏感性差异的机制。本提案中概述的核心实验室、教师指导和培训计划将使我能够在执行这些方法方面开展高级培训，这是我职业道路演变的重要步骤，旨在了解整个动物、器官/组织和分子水平上的胎儿代谢编程机制。这些研究将提供有关 IUGR 胎儿中葡萄糖和乳酸代谢和胰岛素作用以及胎儿肝脏和骨骼肌之间代谢协调的新信息。这些研究还将产生有关信号蛋白早期发展的重要概念，以及将 IUGR 与肝脏中葡萄糖产生增加和胰岛素抵抗联系起来的途径，以及促进骨骼肌中葡萄糖摄取和利用的机制。