Mechanisms of Circadian Rhythmicity in CLOCK-Deficient Mice

时钟缺陷小鼠的昼夜节律机制

基本信息

批准号：
7812113
负责人：
DAVID Raymond WEAVER
金额：
$ 35.15万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-06-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7812113
关键词：
Address Alleles Animals Area Automobile Driving BHLH Protein Back Behavior Behavioral Biochemical Biological Assay Body Temperature Brain Cells Circadian Rhythms Clock protein Complex Development Disease Dominant-Negative Mutation E-Box Elements Elements Event Feedback Financial compensation Gene Expression Gene Expression Regulation Generations Genes Genetic Transcription Helix-Turn-Helix Motifs Homologous Gene Human Jet Lag Syndrome Light Liver Maintenance Mediating Mental Depression Mental disorders Metabolism Molecular Motor Activity Mus Mutant Strains Mice Periodicity Phosphorylation Physiological Play Proteins Reproduction Research Role Seasonal Affective Disorder Sleep Sleep Disorders System Testing Time Transcription Coactivator Transcriptional Activation base cell growth circadian pacemaker cryptochrome dimer feeding molecular phenotype mutant neuropsychiatry novel null mutation protein complex response transcription factor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Circadian rhythms are present in species throughout the animal kingdom. In humans, disorders of circadian timing contribute to circadian-based sleep disorders, maladjustment of shift workers and during jet lag, and may contribute to neuropsychiatric disorders including depression and seasonal affective disorder. A transcriptional-translational feedback loop is at the center of the circadian clock mechanism. The known positive elements driving circadian transcription are CLOCK and BMAL1, two basic helix loop helix proteins that dimerize to activate expression of responsive genes. We have recently generated mice with a null mutation of the Clock gene. Unexpectedly, these CLOCK-deficient mice retain circadian rhythmicity in behavior in constant conditions. Our studies will characterize physiological and molecular rhythms in CLOCK-deficient mice, and assess mechanisms of rhythmicity in the absence of CLOCK. In mice with the previously described dominant negative mutation of Clock, the CLOCK-delta19 protein likely disrupts circadian rhythmicity by interfering with the activity of other key bHLH-PAS proteins, indicating that a major circadian transcriptional activator remains to be identified. A major objective of this project will be to identify this apparent second mechanism for transcriptional activation. We will test the hypothesis that NPAS2, a bHLH-PAS transcription factor closely related to CLOCK, can substitute for CLOCK and thus maintain rhythmicity in CLOCK-deficient mice. We will also determine whether BMAL1 is necessary for rhythmicity in the absence of CLOCK, expecting a finding that will enable studies based on assessment of the functional importance of candidate BMAL1-interacting proteins. The proposed studies are necessary to understand the function of CLOCK, a central component of the circadian clock mechanism, and thus are relevant to understanding and possibly developing novel treatments for circadian-based sleep and psychiatric disorders. In addition, the circadian clock plays diverse roles in regulating reproduction, metabolism, cell growth and tumor progression, so the importance of understanding basic mechanisms of circadian rhythm generation has many implications.

描述（由申请人提供）：整个动物王国的物种中都存在昼夜节律。在人类中，昼夜节律的疾病会导致基于昼夜节律的睡眠障碍，转变工人的不适和喷气滞后期间的疾病，并可能导致神经精神疾病，包括抑郁症和季节性情感障碍。转录 - 翻译反馈回路位于昼夜节律机制的中心。驱动昼夜节律转录的已知阳性元素是时钟和BMAL1，这是两个基本的螺旋环螺旋蛋白，它们二聚而激活反应基因的表达。我们最近产生了小鼠的时钟基因突变。出乎意料的是，这些时钟缺陷的小鼠在恒定条件下保留了行为的昼夜节律。我们的研究将表征时钟缺陷小鼠中的生理和分子节奏，并在没有时钟的情况下评估节奏性的机制。在具有先前描述的时钟显性阴性突变的小鼠中，时钟 - 戴尔塔蛋白可能通过干扰其他关键BHLH-PAS蛋白的活性来破坏昼夜节律的节奏，这表明昼夜节律的主要转录激活剂仍然可以识别。该项目的一个主要目的是确定转录激活的明显第二种机制。我们将检验以下假设：NPAS2是与时钟密切相关的BHLH-PAS转录因子，可以代替时钟，从而保持时钟缺陷小鼠的节奏性。我们还将在没有时钟的情况下确定BMAL1是否对于节奏性是必要的，期望这一发现将基于评估候选BMAL1相互作用蛋白的功能重要性的研究。提出的研究对于了解时钟的功能是必要的，这是昼夜节律时钟机制的核心组成部分，因此与理解和可能开发了基于昼夜节律的睡眠和精神病的新型治疗方法有关。此外，昼夜节律时钟在调节繁殖，代谢，细胞生长和肿瘤进展方面起着不同的作用，因此了解昼夜节律产生基本机制的重要性具有许多影响。