TORC2-dependent regulation of gluconeogensis

描述(申请人提供)：通过协调骨骼肌中的葡萄糖代谢、脂肪组织中的脂肪储存和肝脏中的葡萄糖产生来维持葡萄糖稳态。胰岛素和胰升糖素是葡萄糖稳态的中枢激素调节器。胰高血糖素通过激活cAMP信号通路在肝细胞中启动糖异生程序，而胰岛素则抑制肝脏葡萄糖输出。我们最近的实验发现了cAMP途径的一个新的组成部分，TORCS(Transducers Of Regular CREB)，已经确定了cAMP信号比以前认识的更复杂，并为葡萄糖动态平衡提供了新的见解。总而言之，最近的研究表明，胰岛素、胰升糖素和能量信号会聚在TORC2的磷酸化上，通过CREB介导的肝脏基因表达来调节葡萄糖输出。然而，TORC2的具体核作用尚不清楚。因此，区分TORC2信号的机制具有重要的生物学和临床意义。我们已经确定并证实了内源性TORC2与RNA结合蛋白NONO(P54nrb)之间的一种新的物理相互作用。NONO调节前mRNA的加工，重要的是，我们的初步研究表明，NONO是cAMP信号通路中一个必要的和非冗余的组成部分。我们的发现支持这样的假设，即TORC2通过cAMP靶基因的选择性剪接来控制基因表达和蛋白质生产。我们将验证NONO是肝脏糖异生的必需成分的假设，并将确定TORC2和NONO控制前mRNA处理以维持葡萄糖稳态的机制。2型糖尿病已经达到了大流行的程度，仅在美国就有大约2000万人受到影响。患有2型糖尿病的人要么不能产生足够的胰岛素，要么更常见的是他们的细胞对胰岛素信号变得不敏感，导致葡萄糖稳态失衡。通过研究关键糖异生基因的调控机制，我们将揭示关键的治疗靶点。

DESCRIPTION (provided by applicant): Glucose homeostasis is maintained by coordinating glucose metabolism in skeletal muscle, lipid storage in adipose tissue, and glucose production in the liver. Insulin and glucagon are central hormone regulators of glucose homeostasis. Glucagon initiates the gluconeogenic program in hepatocytes by activating the cAMP signaling pathway, while insulin inhibits hepatic glucose output. Our recent experiments identifying a new component of the cAMP pathway, TORCs (Transducers of Regulated CREB), have established that cAMP signaling is more sophisticated than previously recognized and provide new insights into glucose homeostasis. Collectively, recent studies have demonstrated that insulin, glucagon, and energy signals converge on TORC2 phosphorylation to modulate glucose output via CREB-mediated hepatic gene expression. However, the specific nuclear actions of TORC2 are unknown. Thus, the mechanisms involved in differentiating TORC2-transmitted signals are of important biological and clinical interest. We have identified and confirmed a novel physical interaction between endogenous TORC2 and the RNA binding protein NONO (p54nrb). NONO regulates pre-mRNA processing and, importantly, our Preliminary Studies have demonstrated that NONO is a necessary and non- redundant component of the cAMP signaling pathway. Our findings support the hypothesis that TORC2 controls gene expression and protein production via alternative splicing of cAMP target genes. We will test the hypothesis that NONO is a required component of hepatic gluconeogenesis and will define the mechanism by which TORC2 and NONO control pre-mRNA processing to maintain glucose homeostasis. Type 2 diabetes has reached pandemic proportions with approximately 20 million individuals affected in the United States alone. Individuals suffering from type 2 diabetes either do not produce enough insulin or more commonly their cells become insensitive to insulin signaling resulting in an imbalance in glucose homeostasis. By studying the mechanisms of regulation of key gluconeogenic genes we will uncover key therapeutic targets.