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

描述（由申请人提供）：昼夜节律是生命的组成部分，构成生物化学、生理学和行为的时间模式。这些周期由内源性<24小时周期的内部生物钟驱动。主昼夜节律起搏点位于哺乳动物下丘脑视交叉上核（SCN）。昼夜节律计时系统的紊乱与精神疾病和代谢紊乱有关，理解昼夜节律的神经生物学和生理学应该会导致新的医学治疗方法的发展。我们建议研究DNA结合抑制剂（Id）基因作为哺乳动物昼夜节律系统的潜在调节剂的作用。我们的初步研究表明，Id基因在SCN和外周组织内有节奏地表达; Id 2 null小鼠显示出昼夜节律紊乱表型，包括在大的时区转换后时钟的重新夹带速度加快; ID蛋白抑制已知时钟成分的活性的能力;以及在Id 2 null小鼠中肝脏中正常昼夜节律输出的子集被破坏。我们的研究将集中在1）表征ID 2与经典时钟蛋白CLOCK、BMAL 1和其他相关bHLH转录因子之间的蛋白质-蛋白质相互作用; 2）利用基因和蛋白质表达可视化的传统方法和使用mPER 2-LUCIFERASE小鼠系统的基因/蛋白质表达实时分析来确定所描述表型的分子基础;以及3）研究ID 2在调节时钟输出的转录途径中的作用，重点是小鼠肝脏和代谢系统。预计这些集体研究将提供一个更好的了解Id基因的作用，在哺乳动物的中枢和外周生物钟的分子钟表。

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.