Understanding rhythmic gene regulatory mechanisms in the mammalian circadian system

了解哺乳动物昼夜节律系统中的节律基因调控机制

• 批准号: 10157457
• 负责人: Benjamin Unruh
• 金额: $ 3.87万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10157457
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Animals; Automobile Driving; Behavioral; Bioinformatics; Biological; Biological Process; Biological Rhythm; Brain; Circadian Dysregulation; Circadian Rhythms; Data; Data Set; Diabetes Mellitus; Diagnosis; Diagnostic; Disease; Drosophila genus; Event; Fibroblasts; Gene Expression; Genes; Genetic Transcription; Goals; Half-Life; Head; Health; Human; Intervention; Jet Lag Syndrome; Label; Lead; Life Style; Light; Liver; Malignant Neoplasms; Measures; Melatonin; Messenger RNA; Metabolic; Modernization; Molecular; Mus; Organism; Outcome; Oxidative Stress; Pathway interactions; Periodicity; Phase; Physiological; Planet Earth; Play; Process; RNA; RNA Degradation; RNA chemical synthesis; Regulator Genes; Rotation; Stimulus; System; Techniques; Testing; Time; Tissues; age effect; age related; aged; base; bioinformatics tool; circadian; circadian pacemaker; environmental change; feeding; fly; genome-wide; mRNA Expression; prevent; rate of change; response; shift work; sleep onset; tool; transcriptome; transcriptome sequencing

Summary Circadian rhythms are biological, physiological, and behavioral processes that enable organisms to respond to the environmental changes caused by the rotation of the Earth. Interestingly, recent data started to shed light into the impact of aging on circadian rhythms. For example, circadian processes, such as melatonin secretion and onset of sleep, are phase-advanced in the circadian cycle as humans age. Moreover, the number of rhythmically expressed genes is reduced by 23% in old mouse liver compared to young mouse liver. Furthermore, nearly half of mRNA expressed rhythmically in old mouse liver are not expressed rhythmically in young mouse liver. These data clearly indicate that the aging process changes the molecular mechanisms that drive rhythmic mRNA expression. However, it remains unclear how aging alters the number and identity of rhythmically expressed mRNAs. The goal of this proposal is to understand how the molecular mechanisms that regulate rhythmic gene expression are altered with age and what impact aging has on the circadian cycle. Successful accomplishment of the proposed project will uncover age-related changes to the mechanisms that drive circadian gene expression that are thought to play key roles in driving and maintaining circadian rhythms of various downstream biological processes. For an mRNA to be rhythmically expressed; synthesis, degradation, or a combination of the two must be rhythmic. Additionally, the average mRNA half-life must be short enough for RNA to be newly synthesized each day. In Aim 1, we will experimentally measure circadian changes of mRNA expression, mRNA synthesis and degradation rates both in young and old mouse fibroblasts to evaluate which of these processes is most susceptible to age-related changes in driving rhythmic gene expression. In Aim 2, we will bioinformatically measure circadian changes of mRNA expression, mRNA synthesis degradation rates in fly brain by leveraging circadian RNA-seq datasets that are publicly available. Identification of age-related changes in driving circadian gene expression can ultimately help us develop diagnostic tools and intervention strategies to mitigate circadian disturbances with age. Modern lifestyles contain many stimuli that disrupt the core-clock mechanism such as bright light at night from phones, jet-lag, and night shift work. It is critical that we understand how the mechanisms that drive circadian rhythms change with age to prevent circadian dysregulation that may be exacerbated with age.

概括 昼夜节律是生物、生理和行为过程，使生物体能够 响应地球自转引起的环境变化。有趣的是，最近的数据开始 揭示衰老对昼夜节律的影响。例如，昼夜节律过程，例如褪黑激素 随着人类年龄的增长，内分泌和睡眠开始在昼夜节律周期中处于提前阶段。此外， 与年轻小鼠肝脏相比，老年小鼠肝脏中节律性表达的基因数量减少了 23%。 此外，近一半在老年小鼠肝脏中有节律表达的 mRNA 在小鼠肝脏中没有节律表达。 年轻的小鼠肝脏。这些数据清楚地表明衰老过程改变了分子机制 驱动有节律的 mRNA 表达。然而，目前尚不清楚衰老如何改变细胞的数量和特性。 有节奏地表达 mRNA。该提案的目标是了解分子机制如何 调节节律的基因表达随着年龄的增长而改变，以及衰老对昼夜节律周期的影响。 拟议项目的成功完成将揭示与年龄相关的机制变化 驱动昼夜节律基因表达，这些基因被认为在驱动和维持昼夜节律中发挥关键作用 各种下游生物过程。使 mRNA 有节奏地表达；合成， 退化，或者两者的结合必须是有节奏的。此外，平均 mRNA 半衰期必须为 足够短，以便每天新合成RNA。在目标 1 中，我们将通过实验测量昼夜节律 年轻和年老小鼠mRNA表达、mRNA合成和降解率的变化 成纤维细胞来评估这些过程中哪一个最容易受到驱动节律性的年龄相关变化的影响 基因表达。在目标 2 中，我们将通过生物信息学方法测量 mRNA 表达、mRNA 的昼夜节律变化。 通过利用公开的昼夜节律 RNA-seq 数据集，研究果蝇大脑中的合成降解率。 识别驱动昼夜节律基因表达的年龄相关变化最终可以帮助我们发展 缓解随年龄增长而出现的昼夜节律紊乱的诊断工具和干预策略。现代生活方式 包含许多扰乱核心时钟机制的刺激，例如夜间手机发出的强光、时差、 和夜班工作。至关重要的是我们了解驱动昼夜节律的机制如何变化 随着年龄的增长，以防止昼夜节律失调，这种失调可能会随着年龄的增长而加剧。