TORC2-dependent regulation of gluconeogensis

描述（由申请方提供）：通过协调骨骼肌中的葡萄糖代谢、脂肪组织中的脂质储存和肝脏中的葡萄糖产生来维持葡萄糖稳态。胰岛素和胰高血糖素是葡萄糖稳态的中心激素调节剂。胰高血糖素通过激活cAMP信号通路启动肝细胞中的促凋亡程序，而胰岛素抑制肝葡萄糖输出。我们最近的实验确定了cAMP途径的一个新的组成部分，TORCs（调节CREB的转导子），已经确定cAMP信号传导比以前认识到的更复杂，并提供了对葡萄糖稳态的新见解。总的来说，最近的研究表明，胰岛素，胰高血糖素和能量信号汇聚在TORC 2磷酸化，通过CREB介导的肝脏基因表达调节葡萄糖输出。然而，TORC 2的具体核作用尚不清楚。因此，分化TORC2传递的信号所涉及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TORC 2和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加工，重要的是，我们的初步研究已经证明NONO是cAMP信号通路的必要和非冗余组分。我们的研究结果支持这一假设，即TORC 2控制基因表达和蛋白质的生产通过选择性剪接的cAMP靶基因。我们将检验NONO是肝再生所必需的组分的假设，并将定义TORC 2和NONO控制前mRNA加工以维持葡萄糖稳态的机制。2型糖尿病已达到大流行的程度，仅在美国就有约2000万人受影响。患有2型糖尿病的个体不能产生足够的胰岛素，或者更常见的是，他们的细胞对胰岛素信号不敏感，导致葡萄糖稳态失衡。通过研究关键致瘤基因的调控机制，我们将发现关键的治疗靶点。

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.