Regulation of Hepatic Carbohydrate Metabolism by STBD1

项目总结/摘要 2型糖尿病的发病率正在达到流行病的比例，成为主要的糖尿病之一。 地球仪发病率和死亡率的原因。尽管有进食和禁食期， 在正常人中保持在较低的范围内。一些研究表明， 胰岛素对非氧化性葡萄糖代谢的刺激可能是胰岛素的主要损害之一， 阻力在骨骼肌和心肌中，胰岛素通过一种协调的 葡萄糖转运增加和糖原代谢酶的调节，而肝脏胰岛素阻断 通过抑制糖原生成、促进糖原生成和阻断糖原分解来促进葡萄糖输出。我们 已经发现了一种新的信号通路，涉及泛素化在调节 糖原代谢我们的研究表明，在糖原分解过程中，几种参与其 代谢易位到细胞核，并与E3泛素连接酶Malin相互作用， 蛋白酶体降解另外的研究表明，双特异性磷酸酶Laforin作为一种蛋白酶， 这个过程的分子支架。一个基本的未解之谜是：胰岛素等激素 和胰高血糖素调节这些蛋白质的细胞功能，以及这些新的途径是如何 在代谢性疾病如糖尿病和肥胖症中失调。该提案将解决这些问题。 通过检验胰岛素和胰高血糖素等激素调节胰岛素形成的假设， 糖原相关蛋白质降解中的蛋白质复合物。我们已经确定 STBD 1作为一种新的Laforin相互作用蛋白（STBD 1），可增强糖原合成并与 其他几种糖原相关蛋白。我们的模型表明，STBD 1是关键的组装 针对Malin介导的降解的复合物。我们将测试我们的模型并揭示其机制 通过使用生物化学，细胞和转基因技术的组合来解决这些事件背后的问题， 三个具体目标：（1）评估小鼠肝脏特异性STBD 1表达如何影响全身葡萄糖 （2）研究STBD 1在正常和糖尿病状态下的体内平衡; 通过Malin的糖原相关蛋白的蛋白酶体降解;和（3）确定激素和 调节STBD 1功能的细胞信号。实现这些目标将提供新的见解， 激素控制糖原代谢，以及这一过程如何在代谢紊乱中失调， as diabetes糖尿病and obesity肥胖.重要的是，这可以最终确定新的治疗途径，在这些 疾病 '

Project Summary/Abstract The incidence of type 2 diabetes mellitus is reaching epidemic proportions, becoming one of the major causes of morbidity and mortality across the globe. Despite periods of feeding and fasting, plasma glucose in normal individuals remains in a narow range. Several studies have demonstrated that defects in the stimulation of non-oxidative glucose metabolism by insulin may be among the primary lesions in insulin resistance. In skeletal and cardiac muscle, insulin stimulates glycogen accumulation through a coordinate increase in glucose transport and regulation of glycogen metabolizing enzymes, while in liver insulin blocks glucose output by inhibiting gluconeogenesis, promoting glycogenesis and blocking glycogenolysis. We have made the important discovery of a novel signaling pathway involving ubquitination in the regulation of glycogen metabolism. Our studies demonstrate that during glycogenolysis, several enzymes involved in its metabolism translocate to the nucleus and interact with the E3 ubiquitin ligase Malin for subsequent proteasomal degradation. Additional studies indicate that the dual specificity phosphatase Laforin acts as a molecular scaffold for this process. A fundamental unanswered question is: how hormones such as insulin and glucagon regulate the cellular function of these proteins, and how these novel pathways are dysregulated in metabolic diseases such as diabetes and obesity. This proposal will address these questions by examining the hypothesis that hormones such as insulin and glucagon regulate the formation of protein complexes involved in the degradation of glycogen-associated proteins. We have identified STBD1 as a novel Laforin interacting protein (STBD1) that enhances glycogen synthesis and interacts with several other glycogen associated proteins. Our model suggests that STBD1 is critical for the assembly of complexes targeted for Malin mediated degradation. We will test our model and reveal the mechanisms behind these events by using a combination of biochemical, cellular and transgenic techniques to address three specific aims: (1) to assess how liver specific STBD1 expression in mice affects whole body glucose homeostasis in normal and diabetogenic states; (2) to investigate the role of STBD1 in regulating the proteasomal degradation of glycogen associated proteins by Malin; and (3) to determine the hormonal and cellular signals that regulate STBD1 function. Accomplishing these aims will provide new insight into how hormones control glycogen metabolism, and how this process is dysregulated in metabolic disorders such as diabetes and obesity. Importantly, this can ultimately identify novel therapeutic avenues in these diseases. '