Function of Inhibitor of DNA binding (id) genes in the circadian system

描述(申请人提供)：昼夜节律是生命的一个组成部分，构成生物化学、生理和行为的时间模式。这些周期是由具有内源性24小时周期的内部生物钟驱动的。主要的昼夜节律起搏器位于哺乳动物的下丘脑视交叉上核(SCN)。昼夜节律系统的紊乱已被认为与精神疾病和代谢紊乱有关，了解昼夜节律的神经生物学和生理学将有助于开发新的医学治疗方法。我们建议研究DNA结合(ID)基因的抑制物作为哺乳动物昼夜节律系统的潜在调节器的作用。我们的初步研究表明，ID基因在SCN和外周组织中有节奏地表达；Id2基因缺失的小鼠表现出昼夜节律紊乱的表型，包括在大的时区转换后时钟重新捕获的速度加快；ID蛋白抑制已知时钟成分的活动的能力；以及在Id2缺失的小鼠中，肝脏中正常昼夜输出的一部分被扰乱。我们建议的研究将集中在1)表征ID2与标准时钟蛋白Clock、BMAL1和其他相关bHLH转录因子之间的蛋白质-蛋白质相互作用；2)利用传统的基因和蛋白质表达可视化方法确定所描述的表型的分子基础，并使用mPER2-荧光素酶小鼠系统实时分析基因/蛋白质表达；以及3)研究ID2在调节时钟输出的转录途径中的作用，重点是小鼠的肝脏和代谢系统。预计这些集体研究将提供对ID基因在哺乳动物中央和外周生物钟的分子时钟中的作用的更多了解。公共卫生相关性：昼夜节律系统的紊乱与精神疾病有关，如抑郁症和睡眠障碍，以及代谢紊乱，了解昼夜节律的神经生物学、生理学和分子基础应有助于开发新的治疗方法。我们建议研究DNA结合(ID)基因抑制物作为哺乳动物昼夜节律系统的组成部分的作用。预计这些集体研究将提供对ID转录调节因子在哺乳动物中枢和外周生物钟的分子时钟中的作用的更多了解。

DESCRIPTION (provided by applicant): Circadian rhythms are an integral component of life, structuring temporal patterns of biochemistry, physiology and behavior. These cycles are driven by an internal biological clock with an endogenous <24 hr period. The master circadian pacemaker is located in the mammalian hypothalamic suprachiasmatic nucleus (SCN). Disorders of the circadian timing system have been linked to a mental illness and metabolic disorders and understanding the neurobiology and physiology of circadian rhythms should lead to the development of new medical treatments. We propose to study the role of Inhibitor of DNA-binding (Id) genes as potential modulators of the mammalian circadian system. Our preliminary studies reveal that Id genes are rhythmically expressed within the SCN and peripheral tissues; that Id2 null mice show circadian disorder phenotypes, including an enhanced speed of reentrainment of the clock following a large time-zone transition; the ability for ID proteins to inhibit the activity of known clock components; and that a subset of normal circadian outputs in the liver are disrupted in Id2 null mice. Our proposed research will focus on 1) characterizing the protein-protein interaction between ID2 and canonical clock proteins CLOCK, BMAL1 and other relevant bHLH transcription factors; 2) define the molecular basis for the described phenotypes, utilizing both traditional methods of gene and protein expression visualization, and real-time analysis of gene/protein expression using the mPER2-LUCIFERASE mouse system; and 3) examine the role of ID2 in regulating transcriptional pathways of clock output, focusing upon mouse hepatic and metabolic systems. It is expected that these collective studies will provide a greater understanding of the role of Id genes in the molecular clockwork of the mammalian central and peripheral circadian clocks. PUBLIC HEALTH RELEVANCE: Disorders of the circadian timing system have been linked to mental illness, such as depression and sleep disorders, and metabolic disorders, and understanding the neurobiology, physiology and molecular basis of circadian rhythms should lead to the development of new treatments. We propose to study the role of Inhibitor of DNA-binding (Id) genes as components of the mammalian circadian system. It is expected that these collective studies will provide greater understanding of the role of ID transcriptional regulators in the molecular clockwork of the mammalian central and peripheral circadian clocks.