The effects of metabolic dysfunction on phosphoregulation of the circadian clock

描述（由申请人提供）：代谢紊乱如糖尿病和肥胖影响数百万人。2型糖尿病（T2 D）是最常见的糖尿病形式，其中对胰岛素信号传导的抵抗导致高血糖症和其他并发症。T2 D也与昼夜节律紊乱相关，但因果关系知之甚少。增加的O-连接糖基化（O-GlcNAc化）是T2 D和昼夜节律之间网络中的常见联系。通常，一部分葡萄糖在己糖胺生物合成途径（HBP）中代谢，形成尿苷二磷酸N-乙酰葡萄糖胺（UDP-GlcNAc），O-GlcNAc酰化的供体分子。在稳态条件下，O-GlcNAc酰化和磷酸化是平衡的并调节蛋白质活性。因此，O-GlcNAc化作为葡萄糖敏感性调节剂发挥作用。由于高血糖症增加UDP-GlcNAc和O-GlcNAc化水平，因此产生的高糖基化可影响磷酸化并调节蛋白质活性。昼夜节律和关键时钟蛋白在24小时周期内受到磷酸化的严格调节，破坏这种生化循环与代谢紊乱和抑郁症有关。然而，目前的证据未能描述T2 D诱导的昼夜节律破坏的机制。我建议阐明T2 D诱导的昼夜节律中断的机制，使用遗传和代谢的方法在T2 D苍蝇模型系统，特别关注的生物钟和时钟激酶的翻译后调节。我假设T2 D将增加O-GlcNAc化，减少磷酸化，并改变调节生物钟的特定蛋白质和激酶的活性。通过调查 O-GlcNAc酰化在生物钟调节中的作用，可以确定新的诊断特征和治疗靶点，用于干预T2 D风险、病理和并发症。

DESCRIPTION (provided by applicant): Metabolic disorders such as diabetes and obesity affect millions of people. Type 2 Diabetes (T2D) is the most common form of diabetes in which resistance to insulin signaling causes hyperglycemia and other complications. T2D is also correlated with circadian rhythm disruption, but the causative relationship is poorly understood. Increased O-linked glycosylation (O-GlcNAcylation) is a common link in the network between T2D and circadian rhythm. Typically, a portion of glucose is metabolized in the hexosamine biosynthetic pathway (HBP) and forms Uridine Diphosphate N-Acetyl Glucosamine (UDP-GlcNAc), a donor molecule for O- GlcNAcylation. Under homeostatic conditions, O-GlcNAcylation and phosphorylation are balanced and regulate protein activities. Thus, O-GlcNAcylation behaves as a glucose-sensitive regulator. Since hyperglycemia increases UDP-GlcNAc and O-GlcNAcylation levels, the resultant hyper-glycosylation can affect phosphorylation and modulate protein activity. Circadian rhythm and key clock proteins are tightly regulated by phosphorylation on a 24-hour cycle and disrupting this biochemical cycle correlates to metabolic disorders and depression. However, current evidence fails to describe mechanisms for T2D-induced circadian rhythm disruption. I propose to elucidate mechanisms of T2D-induced circadian rhythm disruption using genetic and metabolic approaches in a T2D fly model system with special focus on the posttranslational regulation of the circadian clock and clock kinases. I hypothesize that T2D will increase O-GlcNAcylation, reduce phosphorylation, and alter activities of specific proteins and kinases that modulate the clock. By investigating the role of O-GlcNAcylation in circadian clock regulation, new diagnostic profiles and therapeutic targets may be identified for the intervention of T2D risks, pathologies, and complications.