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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：哺乳动物的进食行为是间歇性的和昼夜节律的。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 通路通过顺式作用 cAMP 响应元件 (CRE) 调节糖异生基因的转录，以响应禁食和进食的情况。与此同时，自我维持的肝脏生物钟介导代谢基因表达的昼夜节律——其中许多基因受 CREB 和 CRTC2 调节——峰值水平与一天中的适当时间一致。尽管生物钟和 CREB/CRTC2 通路之间的分子相互作用被认为影响了对喂养方案的整体适应，但这些相互作用尚未明确定义。核心生物钟基于转录反馈环，其中 Clock/Bamal1 转录激活剂与 Per 和 Cry 基因启动子中的顺式作用 E-box 结合，其蛋白质产物反过来抑制 Clock/Bmal1 功能，从而在体内产生昼夜节律。 Per 和 Cry 蛋白。当前的应用测试了这样的假设：生物钟和 CREB 通路通过 Per/CRY 抑制剂和 CREB/CRTC2 激活剂之间的相互调节相互作用促进代谢适应环境变化。目标 1 至 3 阐述了 Cry 蛋白在响应间歇性进食而对肝脏 CREB 和 CRTC2 活性进行昼夜节律调节中的作用。特别是，我们将评估 Crys 在减弱胰高血糖素依赖性 cAMP 产生增加方面的作用。细胞质 Cry 是否会干扰 G 蛋白偶联受体信号传导？目标 4-6 解决 CREB/CRTC2 通路对时钟活动的反调节作用。特别是，我们将研究 Per 基因上 CREB 结合位点的调节重要性，它提供了一个同步 Per 转录的节点，从而使生物钟与每日喂养节律同步。最后，我们将测试这些相互作用如何影响生物体对喂养方案的长期适应。