The effects of metabolic dysfunction on phosphoregulation of the circadian clock

代谢功能障碍对生物钟磷酸调节的影响

• 批准号: 9087006
• 负责人: Adam Joseph Contreras
• 金额: $ 3.77万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9087006
• 关键词: Affect; Animal Model; Antibodies; Behavioral; Biochemical; Biological Assay; Biological Models; Circadian Rhythms; Clock protein; Defect; Diabetes Mellitus; Diagnostic; Diet; Dietary Intervention; Drosophila genus; Drosophila melanogaster; Equilibrium; Etiology; Exhibits; Functional disorder; Genetic; Genetic Models; Glucose; Goals; Hexosamines; Hour; Hyperglycemia; Immunoblotting; In Vitro; Insulin Resistance; Insulin Signaling Pathway; Intervention; Investigation; Label; Lead; Link; Metabolic; Metabolic Diseases; Modeling; Modification; Motor Activity; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathology; Pathway interactions; Periodicity; Phosphorylation; Phosphotransferases; Post-Translational Protein Processing; Post-Translational Regulation; Protein Kinase; Proteins; Proto-Oncogene Proteins c-akt; Regulation; Resistance; Risk; Role; Serine; Serine/Threonine Phosphorylation; Testing; Threonine; UDP-glucosamine; Uridine Diphosphate; blood glucose regulation; circadian pacemaker; diabetes risk; diabetic; fly; genetic manipulation; glycosylation; in vivo; insulin signaling; metabolic depression; novel diagnostics; programs; public health relevance; response; sugar; therapeutic target; transcriptome

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.

描述(申请人提供)：糖尿病和肥胖症等代谢障碍影响数百万人。2型糖尿病(T2D)是最常见的糖尿病形式，对胰岛素信号的抵抗会导致高血糖和其他并发症。T2D也与昼夜节律紊乱相关，但其因果关系知之甚少。增强的O-连接糖基化(O-GlcN酰化)是T2D和昼夜节律网络中常见的连接。通常情况下，葡萄糖的一部分在己糖胺生物合成途径(HBP)中代谢，形成尿苷二磷酸N-乙酰氨基葡萄糖(UDP-GlcNAc)，O-GlcN酰化的供体分子。在动态平衡条件下，O-GlcN酰化和磷酸化是平衡的，并调节蛋白质的活性。因此，O-GlcN酰化是一种葡萄糖敏感的调节因子。由于高血糖增加了UDP-GlcNAc和O-GlcN酰化水平，由此产生的高糖化可以影响磷酸化并调节蛋白质的活性。昼夜节律和关键时钟蛋白受到24小时周期磷酸化的严格调控，扰乱这一生化周期与代谢紊乱和抑郁症相关。然而，目前的证据不能描述T2D诱导的昼夜节律紊乱的机制。我建议在一个T2D苍蝇模型系统中用遗传和代谢方法来阐明T2D诱导的昼夜节律紊乱的机制，特别是对生物钟和时钟激酶的翻译后调节。我假设T2D会增加O-GlcN酰化，减少磷酸化，并改变调节时钟的特定蛋白质和激酶的活性。通过调查 O-GlcN酰化在生物钟调节中的作用、新的诊断特征和治疗靶点可能被确定用于T2D风险、病理和并发症的干预。