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Hormonal Regulation of Glycogen Synthesis

糖原合成的激素调节

基本信息

批准号：
7762696
负责人：
ALAN R. SALTIEL
金额：
$ 30.46万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-02-15 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7762696
关键词：
Attention Attenuated Binding Biological Assay Cataloging Catalogs Cells Characteristics Chimera organism Cyclic AMP Data Defect Development Diabetes Mellitus Disease Energy Metabolism Enzymes Epidemic Evaluation Funding Future Genes Glucose Glycogen Glycogen Storage Disease Hepatocyte Hereditary Disease Hormones Insulin Insulin Resistance Investigation Laboratories Lafora Disease Liver Modeling Molecular Multienzyme Complexes Mus Muscle Muscle Cells Mutation Normal Cell Normal tissue morphology Pathway interactions Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Physiological Primary Lesion Process Protein phosphatase Proteins Regulation Role Scaffolding Protein Series Signal Pathway Small Interfering RNA Specificity Staging Structure Surface Plasmon Resonance Surveys Uncertainty Work deprivation enzyme activity glucose metabolism glycogen metabolism glycogenesis glycogenolysis hormone regulation in vivo knock-down mutant overexpression protein complex protein function trait

项目摘要

DESCRIPTION (provided by applicant): There is little doubt that we are in the midst of a worldwide epidemic of diabetes. Insulin resistance is recognized as a characteristic trait of the disease, defined by the inability to respond to normal circulating levels of insulin. The primary lesion in this state involves defects in the nonoxidative metabolism of glucose, expressed as glycogen accumulation in muscle and liver, and may also involve changes in the branching structure of glycogen. Moreover, glycogen storage diseases involve aberrations in glycogen synthesis, degradation, branching and debranching. We have studied glycogen scaffolding proteins that target enzymes involved in glycogen metabolism, and uncovered a role in controlling glycogen debranching. In Aim 1, we will study the signaling pathways involved in glycogen debranching, focusing on the regulation of the debranching enzyme AGL. We will investigate how hormones or glucose deprivation might influence the phosphorylation state and activity of this enzyme. In Aim 2, we will evaluate how the glycogen targeting protein PTG influences glycogen metabolism via AGL. PTG can interact directly with AGL, and we will explore the regulatory significance of this interaction, evaluating the control of localization and activity in detail. Finally, in Aim 3, we will evaluate the role of a dual specificity protein phosphatase called Laforin in regulating glycogen metabolism and branching. Laforin dynamically regulates AGL along with PTG. The protein is encoded by the gene that causes Lafora's disease, a genetic disease in which unbranched glycogen accumulates, thus providing important hints into how this process is regulated in normal tissues. We will search for additional substrates of Laforin to explore other ways in which this protein regulates glycogen synthesis. Together, these approaches will allow for the evaluation of how glycogen metabolism is regulated in liver and muscle, setting the stage for future investigations into its potential role in the development of diabetes and other disorders of energy metabolism.

描述（由申请人提供）：毫无疑问，我们正处于世界范围内的糖尿病流行之中。胰岛素抵抗被认为是该疾病的一个特征，其定义是无法对正常循环的胰岛素水平做出反应。这种状态的主要病变涉及葡萄糖非氧化代谢的缺陷，表现为肌肉和肝脏中糖原的积累，也可能涉及糖原分支结构的变化。此外，糖原贮积病涉及糖原合成、降解、分支和脱支的异常。我们研究了针对参与糖原代谢的酶的糖原支架蛋白，并揭示了其在控制糖原脱支中的作用。在目标 1 中，我们将研究糖原脱支所涉及的信号通路，重点关注脱支酶 AGL 的调节。我们将研究激素或葡萄糖剥夺如何影响这种酶的磷酸化状态和活性。在目标 2 中，我们将评估糖原靶向蛋白 PTG 如何通过 AGL 影响糖原代谢。 PTG可以直接与AGL相互作用，我们将探讨这种相互作用的调控意义，详细评估定位和活性的控制。最后，在目标 3 中，我们将评估称为 Laforin 的双特异性蛋白磷酸酶在调节糖原代谢和分支中的作用。 Laforin 与 PTG 一起动态调节 AGL。这种蛋白质是由引起拉福拉氏病的基因编码的，拉福拉氏病是一种无分支糖原积累的遗传性疾病，因此为了解正常组织中如何调节这一过程提供了重要线索。我们将寻找 Laforin 的其他底物，以探索该蛋白质调节糖原合成的其他方式。总之，这些方法将允许评估肝脏和肌肉中糖原代谢的调节方式，为未来研究其在糖尿病和其他能量代谢疾病的发展中的潜在作用奠定基础。