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

DNA 结合抑制剂 (id) 基因在昼夜节律系统中的功能

• 批准号: 7987653
• 负责人: Giles Duffield
• 金额: $ 29.06万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7987653
• 关键词: Affect; Behavior; Behavioral; Binding; Biochemical; Biochemistry; Biological Assay; Biological Clocks; Brain; Circadian Rhythms; Clock protein; Co-Immunoprecipitations; DNA Binding; Development; Disease; Embryo; Environment; Event; Feedback; Fibroblasts; Fluorescence; Gene Expression; Gene Proteins; Genes; Genetic Transcription; Goals; Health; Hepatic; Hour; Human; Hybrids; Hypothalamic structure; ID2 gene; Imagery; Individual; Knockout Mice; Lead; Life; Link; Liver; Luciferases; Medical; Mental Depression; Mental disorders; Messenger RNA; Metabolic; Metabolic Diseases; Methods; Molecular; Molecular Genetics; Monitor; Motor Activity; Mus; Mutation; Nature; Neurobiology; Organ; Organism; Output; Pacemakers; Pathway interactions; Pattern; Peripheral; Phase; Phenotype; Physiological; Physiology; Proteins; Regulation; Regulatory Element; Reporter Genes; Research; Research Design; Role; Series; Sleep Disorders; Slice; Speed; Structure; System; Techniques; Testing; Time; Tissues; base; chromatin immunoprecipitation; circadian pacemaker; cohort; follow-up; in vivo; inhibitor/antagonist; interest; lipid metabolism; molecular phenotype; mutant; operation; promoter; protein expression; protein protein interaction; public health relevance; research study; response; suprachiasmatic nucleus; transcription factor

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.

描述（由申请人提供）：昼夜节律是生命不可或缺的组成部分，构建生物化学、生理学和行为的时间模式。这些周期由内部生物钟驱动，内源性<24 小时周期。主昼夜节律起搏器位于哺乳动物下丘脑视交叉上核（SCN）。昼夜节律系统的紊乱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应该有助于开发新的医学治疗方法。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 和外周组织内有节律地表达； Id2缺失小鼠表现出昼夜节律紊乱表型，包括在大的时区转换后时钟重新调整的速度加快； ID蛋白抑制已知时钟成分活性的能力；并且 Id2 缺失小鼠肝脏中正常昼夜节律输出的一部分被破坏。我们提出的研究将集中于 1) 表征 ID2 与经典时钟蛋白 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) 利用基因和蛋白质表达可视化的传统方法以及使用 mPER2-LUCIFERASE 小鼠系统实时分析基因/蛋白质表达，定义所述表型的分子基础； 3) 研究 ID2 在调节时钟输出转录途径中的作用，重点关注小鼠肝脏和代谢系统。预计这些集体研究将有助于更好地了解 Id 基因在哺乳动物中枢和外周生物钟的分子时钟中的作用。公共卫生相关性：昼夜节律系统的紊乱与精神疾病有关，例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该有助于开发新的治疗方法。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组成部分的作用。预计这些集体研究将有助于更好地了解 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。