TORC2-dependent regulation of gluconeogensis

描述（由申请人提供）：葡萄糖稳态是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生成来维持的。胰岛素和胰高血糖素是调节葡萄糖稳态的中枢激素。胰高血糖素通过激活cAMP信号通路启动肝细胞的糖异生程序，而胰岛素抑制肝脏葡萄糖输出。我们最近的实验确定了cAMP途径的一个新组分，TORCs（受调节CREB的转导器），已经确定了cAMP信号传导比以前认识到的更复杂，并为葡萄糖稳态提供了新的见解。总的来说，最近的研究表明，胰岛素、胰高血糖素和能量信号聚集在TORC2磷酸化上，通过creb介导的肝脏基因表达调节葡萄糖输出。然而，TORC2的具体核作用尚不清楚。因此，分化torc2传递信号的机制具有重要的生物学和临床意义。我们已经发现并证实了内源性TORC2和RNA结合蛋白NONO （p54nrb）之间的一种新的物理相互作用。NONO调节pre-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成分。我们的研究结果支持了TORC2通过cAMP靶基因的选择性剪接控制基因表达和蛋白质产生的假设。我们将验证NONO是肝脏糖异生的必要组成部分的假设，并将确定TORC2和NONO控制mrna前加工以维持葡萄糖稳态的机制。2型糖尿病已达到流行病的比例，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.