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：
7435278
负责人：
DAVID Raymond WEAVER
金额：
$ 35.5万
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 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7435278
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 Condition Development Disease Disruption 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 Phenotype 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 mutant neuropsychiatry novel null mutation 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）：昼夜节律存在于整个动物界的物种中。在人类中，昼夜节律紊乱会导致基于昼夜节律的睡眠障碍、轮班工人和时差反应失调，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-翻译反馈环路位于生物钟机制的中心。驱动昼夜节律转录的已知正向元件是 CLOCK 和 BMAL1，这两种基本螺旋环螺旋蛋白可二聚化以激活响应基因的表达。我们最近培育出了时钟基因无效突变的小鼠。出乎意料的是，这些时钟缺陷小鼠在恒定条件下保持了行为的昼夜节律。我们的研究将描述 CLOCK 缺陷小鼠的生理和分子节律特征，并评估 CLOCK 缺失情况下的节律机制。在具有先前描述的 Clock 显性失活突变的小鼠中，CLOCK-delta19 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，这表明主要的昼夜节律转录激活因子仍有待鉴定。该项目的一个主要目标是确定转录激活的第二种明显机制。我们将检验这样的假设：NPAS2（一种与 CLOCK 密切相关的 bHLH-PAS 转录因子）可以替代 CLOCK，从而维持 CLOCK 缺陷小鼠的节律性。我们还将确定 BMAL1 在没有 CLOCK 的情况下是否是节律所必需的，期待这一发现能够使基于评估候选 BMAL1 相互作用蛋白的功能重要性的研究成为可能。拟议的研究对于了解生物钟机制的核心组成部分 CLOCK 的功能是必要的，因此与理解和可能开发针对基于昼夜节律的睡眠和精神疾病的新疗法有关。此外，生物钟在调节生殖、代谢、细胞生长和肿瘤进展方面发挥着多种作用，因此了解昼夜节律产生的基本机制的重要性具有许多意义。