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：
8638961
负责人：
MARC R MONTMINY
金额：
$ 62.71万
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/8638961
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）：哺乳动物的喂养行为既是情节性和昼夜节律。因此，哺乳动物已经开发出一种机制，可以在时间上调节肝糖异生，以维持葡萄糖稳态。 CREB/CRTC2途径通过顺式作用CAMP反应元件（CRE）调节糖原基因的转录，以响应禁食和喂食。同时，自维持的肝昼夜节律时钟在代谢基因的表达中介导了昼夜节律 - 其中许多受CREB和CRTC2-调节，峰值水平与一天中的适当时间保持一致。尽管昼夜节律时钟与CREB/CRTC2途径之间的分子相互作用被认为可以影响对喂养方案的整体适应性，但这些相互作用尚未得到很好的定义。核心昼夜节律时钟基于转录反馈回路，其中时钟/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，其蛋白质产物又抑制了时钟/BMAL1功能，从而在Per和Cry蛋白质中产生昼夜节律节奏。当前的申请检验了以下假设：昼夜节律时钟和CREB途径通过每/cry抑制剂与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。目的1到3解决了哭泣蛋白在肝脏CREB和CRTC2活性的昼夜节律调节中的作用。特别是，我们将评估CRY在减弱胰高血糖素依赖性增加中的拟议作用。细胞质哭泣会干扰G蛋白偶联受体信号传导吗？ AIMS 4-6解决CREB/CRTC2途径对时钟活动的反调节效应。特别是，我们将研究CREB结合位点对每个基因的调节重要性，该基因为每个转录同步提供了一个节点，因此，昼夜节律时钟与日常喂养节奏。最后，我们将测试这些相互作用如何塑造生物体对喂养方案的长期适应性。