Understanding rhythmic gene regulatory mechanisms in the mammalian circadian system

总结 昼夜节律是生物、生理和行为过程，使生物体能够 对地球自转引起的环境变化作出反应。有趣的是，最近的数据开始 揭示了衰老对昼夜节律的影响。例如，昼夜节律过程，如褪黑激素 分泌和睡眠的开始，随着人类年龄的增长，在昼夜节律周期中处于提前阶段。而且 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，在老年小鼠肝脏中有节律表达的mRNA中，近一半在老年小鼠肝脏中没有节律表达。 幼鼠肝脏。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，目前还不清楚衰老如何改变这些细胞的数量和身份。 有节奏地表达mRNA。这项提案的目标是了解如何分子机制， 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。 成功完成拟议的项目将揭示与年龄有关的机制变化， 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起关键作用 各种下游生物过程。对于mRNA有节奏地表达，合成， 退化，或两者的结合必须是有节奏的。此外，平均mRNA半衰期必须是 短到每天都能合成新的RNA。在目标1中，我们将通过实验测量昼夜节律， 青年和老年小鼠mRNA表达、mRNA合成和降解速率的变化 成纤维细胞，以评估这些过程中的哪一个最容易受到年龄相关的驾驶节奏变化的影响。 基因表达。在目标2中，我们将生物信息学测量mRNA表达的昼夜变化，mRNA 通过利用公开可用的昼夜节律RNA-seq数据集，研究果蝇大脑中的合成降解速率。 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 诊断工具和干预策略，以减轻随着年龄的昼夜节律紊乱。现代生活方式 包含许多干扰核心时钟机制的刺激，例如夜间手机发出的强光，时差， 还有夜班工作我们必须了解驱动昼夜节律变化的机制 以防止可能随着年龄的增长而加剧的昼夜节律失调。

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.