Cross-talk between the circadian clock and the cAMP signaling pathway

生物钟和 cAMP 信号通路之间的串扰

• 批准号: 8449748
• 负责人: MARC R MONTMINY
• 金额: $ 60.51万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8449748
• 关键词: Address; Adenylate Cyclase; Affect; Attenuated; Binding; Binding Sites; Boxing; CREB1 gene; Cell Nucleus; Cell Surface Receptors; Circadian Rhythms; Crying; Cyclic AMP; Cyclic AMP Response Element; Cytoplasm; Fasting; Feedback; Feeding Patterns; Feeding behaviors; G Protein-Coupled Receptor Genes; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Genetic screening method; Glucagon; Gluconeogenesis; Hepatic; Homeostasis; Indium; Insulin Resistance; Intervention; Ligands; Liver; Mammals; Measures; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Molecular; Mutant Strains Mice; Nutrient; Organism; Pathway interactions; Performance; Phase; Prevention; Production; Proteins; Receptor Signaling; Regimen; Risk; Role; Shapes; Signal Pathway; Site; Testing; Time; Tissues; Transcription Coactivator; base; blood glucose regulation; circadian pacemaker; cryptochrome; environmental change; feeding; hepatic gluconeogenesis; inhibitor/antagonist; insight; programs; promoter; public health relevance; response

DESCRIPTION (provided by applicant): Feeding behavior in mammals is both episodic and circadian. Accordingly, mammals have developed mechanisms to temporally regulate liver gluconeogenesis to maintain glucose homeostasis. The CREB/CRTC2 pathway regulates transcription of gluconeogenic genes via cis-acting cAMP Response Elements (CREs) in response to fasting and feeding bouts. In parallel, the self sustaining hepatic circadian clock mediates circadian rhythm in expression of metabolic genes- a number of which are regulated by CREB and CRTC2- with peak levels aligned to appropriate time of the day. Although molecular interactions between the circadian clock and the CREB/CRTC2 pathway are thought to shape the overall adaptation to feeding regimen, these interactions are not well defined. The core circadian clock is based on a transcriptional feedback loop in which Clock/Bamal1 transcriptional activators bind to cis acting E-box in the promoters of Per and Cry genes, whose protein products in turn inhibit Clock/Bmal1 function, thus producing circadian rhythms in Per and Cry proteins. The current application tests the hypothesis that the circadian clock and CREB pathway promote metabolic adaptation to environmental changes through reciprocal regulatory interactions between the Per/CRY inhibitors and CREB/CRTC2 activators. Aims 1 to 3 address the role of Cry proteins in the circadian modulation of hepatic CREB and CRTC2 activities in response to episodic feeding. In particular, we will evaluate the proposed role of Crys in attenuating glucagon-dependent increases in cAMP production. Does cytoplasmic Cry interfere with G protein coupled receptor signaling? Aims 4-6 address counter-regulatory effects of the CREB/CRTC2 pathway on clock activity. In particular, we will examine the regulatory importance of CREB binding sites on Per genes, which offer a node for synchronizing Per transcription and consequently the circadian clock with the daily feeding rhythms. Finally, we will test how these interactions shape long term adaptation of the organism to feeding regimens.

描述(申请人提供)：哺乳动物的摄食行为既有间歇性又有昼夜节律。因此，哺乳动物已经发展出暂时调节肝脏糖异生以维持葡萄糖稳态的机制。CREB/CRTC2途径通过顺式作用的cAMP反应元件(Cres)调节糖异生基因的转录，以响应禁食和摄食。同时，自我维持的肝脏生物钟调节代谢基因表达的昼夜节律--其中许多基因受CREB和CRTC2调节--峰值水平与一天中适当的时间一致。尽管生物钟和CREB/CRTC2途径之间的分子相互作用被认为塑造了对摄食方案的整体适应，但这些相互作用并未得到很好的定义。核心生物钟基于转录反馈环，在该环中，Clock/Bamal1转录激活子与Per和Cry基因启动子中顺式作用的E-box结合，后者的蛋白产物反过来抑制Clock/BMal1的功能，从而在Per和Cry蛋白中产生昼夜节律。目前的应用验证了这样的假设，即生物钟和CREB途径通过PER/CRY抑制剂和CREB/CRTC2激活剂之间的相互调节作用促进代谢对环境变化的适应。目标1至3说明Cry蛋白在肝脏CREB和CRTC2活性的昼夜节律调节中的作用。特别是，我们将评估Crys在减轻cAMP产生的依赖于胰高血糖素的增加方面的拟议作用。胞质Cry干扰G蛋白偶联受体信号转导吗？AIMS 4-6解决CREB/CRTC2通路对时钟活动的反调节效应。特别是，我们将检查CREB结合位点在PER基因上的调节重要性，它为PER转录提供了一个节点，从而使生物钟与日常摄食节律同步。最后，我们将测试这些相互作用如何形成生物体对摄食方案的长期适应。