Hormonal Regulation of Glycogen Synthesis

糖原合成的激素调节

• 批准号: 7010747
• 负责人: ALAN R. SALTIEL
• 金额: $ 30.99万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-15 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7010747
• 关键词: CHO cells; adipocytes; biological signal transduction; birth; chimeric proteins; enzyme activity; gene targeting; genetically modified animals; glucose metabolism; glycogen; glycogen synthase; glycogenesis; glycogenolysis; hormone regulation /control mechanism; hypoglycemia; insulin; laboratory mouse; lipid metabolism; liver cells; muscle cells; mutant; phosphatidylinositol 3 kinase; phosphoprotein phosphatase; phosphorylases; phosphorylation; protein structure function; yeast two hybrid system

There is little doubt that we are in the midst of a worldwide epidemic of diabetes. Almost 16 million people in the US are thought to be afflicted, a third of whom are undiagnosed. 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 uptake and storage of glucose in muscle and fat cells. Targeting these defects holds the key to the development of new therapeutic approaches. However, understanding the specific lesions that cause insulin resistance in patients with type 2 diabetes will first require a better grasp of the cell biology of insulin action. To this end, the molecular events involved in the regulation of glycogen synthesis by insulin will be investigated, with special attention to the role of a newly described scaffolding protein, PTG, in the regulation of protein dephosphorylation. In Aim l, the molecular basis for the existence of multiple scaffolding proteins for protein phosphatase 1 (PP1) will be investigated, evaluating the hypothesis that each member of this family has a defined separate function in signal transduction. The structure/function relationships of these molecules will be analyzed by a series of deletion and chimeric mutants. This will be followed by evaluation of the effects of the mutants on glycogen metabolism in cell models, and in intact rat liver. Aim 2 will focus on dissecting the signaling pathway that mediates the activation of PP1 by insulin at the glycogen pellet, resulting in the stimulation of glycogen synthase. This approach will pursue two novel hypotheses involving the identification of regulatory proteins that might be substrates for phosphorylation. The physiological function of PTG will be investigated in Aim 3, by the targeted disruption of the PTG gene in mice. Together, these approaches will allow for the evaluation of the importance of this pathway in insulin action, setting the stage for future investigations into its potential role in the development of diabetes.

毫无疑问，我们正处于糖尿病的全球流行之中。 据信，美国有近1600万人患有这种疾病，其中三分之一未被确诊。胰岛素抵抗被认为是该疾病的特征，其定义为不能对正常循环水平的胰岛素作出反应。 这种状态下的原发性病变涉及肌肉和脂肪细胞中葡萄糖摄取和储存的缺陷。 针对这些缺陷是开发新治疗方法的关键。 然而，了解导致2型糖尿病患者胰岛素抵抗的特定病变首先需要更好地掌握胰岛素作用的细胞生物学。 为此，参与胰岛素糖原合成的调节的分子事件将进行调查，特别注意一个新描述的支架蛋白，PTG，在蛋白质去磷酸化的调节中的作用。 在目的1中，将研究蛋白磷酸酶1（PP 1）的多个支架蛋白存在的分子基础，评估该家族的每个成员在信号转导中具有确定的单独功能的假设。 这些分子的结构/功能关系将通过一系列缺失和嵌合突变体进行分析。 随后将评价突变体对细胞模型和完整大鼠肝脏中糖原代谢的影响。 目的2将集中于解剖的信号通路，介导的激活PP 1的胰岛素在糖原颗粒，导致在糖原合成酶的刺激。 这种方法将追求两个新的假设，涉及到可能是磷酸化底物的调节蛋白的鉴定。 目的3将通过靶向破坏小鼠中的PTG基因来研究PTG的生理功能。 总之，这些方法将允许评估该途径在胰岛素作用中的重要性，为未来研究其在糖尿病发展中的潜在作用奠定基础。