Hormonal Regulation of Glycogen Synthesis

描述(由申请人提供)：毫无疑问，我们正处于糖尿病的全球流行之中。胰岛素抵抗被认为是这种疾病的一个特征，其定义是无法对正常的循环胰岛素水平做出反应。这种状态下的原发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聚，也可能涉及糖原分支结构的变化。此外，糖原储存疾病涉及糖原合成、降解、分支和去分支的异常。我们已经研究了糖原支架蛋白，目标是参与糖原代谢的酶，并发现了在控制糖原去分支中的作用。在目标1中，我们将研究参与糖原去支化的信号通路，重点是去支化酶AGL的调节。我们将研究激素或缺糖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可以与AGL直接相互作用，我们将探索这种相互作用的调控意义，详细评估对本地化和活性的控制。最后，在目标3中，我们将评估一种称为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。拉福林与PTG一起动态调节AGL。这种蛋白质是由导致拉福拉病的基因编码的，拉福拉病是一种遗传性疾病，在这种疾病中，未分枝的糖原积累，从而为这一过程在正常组织中如何调控提供了重要线索。我们将寻找拉福林的其他底物，以探索该蛋白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是如何调节的，为未来研究糖原在糖尿病和其他能量代谢紊乱中的潜在作用奠定了基础。

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.