Investigating Circadian Post-Transcriptional Regulation.

研究昼夜节律转录后调节。

• 批准号: 10621067
• 负责人: Jennifer Hurley
• 金额: $ 42.34万
• 依托单位: RENSSELAER POLYTECHNIC INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621067
• 关键词: Address; Architecture; Biological Clocks; Biological Models; Biological Process; Biophysics; Cell physiology; Chronic; Circadian Dysregulation; Circadian Rhythms; Complex; Development; Disease; Ensure; Feedback; Gene Expression; Genetic Transcription; Goals; Health; Hour; Human; Immune; Immune response; Inflammation; Investigation; Link; Macromolecular Complexes; Malignant Neoplasms; Maps; Medical; Messenger RNA; Metabolic; Metabolic Diseases; Metabolism; Molecular; Molecular Conformation; Multiprotein Complexes; Mus; Output; Pathway interactions; Periodicity; Physiological; Physiology; Post-Transcriptional Regulation; Process; Proteins; Regulation; Reproducibility; Research; Sleep; Source; Testing; Time; Tissues; Transcriptional Regulation; Translations; circadian; circadian pacemaker; circadian regulation; cost; fitness; molecular clock; novel; posttranscriptional; protein complex; sex

Project Summary/Abstract: Circadian rhythms are highly conserved, 24-hour, oscillations that tune human physiology to the day/night cycle, enhancing fitness by ensuring that appropriate activities occur at biologically advantageous times. Disruption of proper circadian timing negatively impacts the human long-term medical outlook, making understanding the mechanism underlying circadian regulation over cellular physiology critical to human health. Circadian rhythms are controlled via a transcription-translation based negative feedback loop, or clock. The current paradigm for circadian regulation over physiology, termed the clocks “output”, is that transcriptional programing generated by the clock drives temporally-specific waves of gene expression. However, our research has revealed that transcriptional programing cannot wholly account for clock output, as we discovered weak correlation between mRNAs and proteins that oscillate with a circadian periodicity, particularly in the circadian regulation of immunometabolism. The mechanisms that control this post-transcriptional regulation are unknown, but we have shown that intrinsic protein disorder in the repressive complex of the clock may control the formation of macromolecular complexes to time clock output post-transcriptionally. Our immediate research goal is to identify specific pathways by which the clock imparts post- transcriptional control over the immune response at the biophysical, molecular, and physiological levels. We hypothesize that circadian post-transcriptional metabolic regulation can tune immune-tissue and sex-specific rhythms via the formation of time-of-day defined macromolecular protein complexes that are centered around the repressive complex of the circadian clock. To test this hypothesis, we will create a Conformational/Temporal Interactome (CiTI) map of circadian repressive complex proteins. We will also investigate the contribution of sex-specific metabolic post-transcriptional regulation to immune cell functions to demonstrate the effects of metabolic oscillations on the basal immune response. As a mechanism for keeping time, circadian feedback loops are highly conserved and much of what is understood about the molecular clock comes from the investigation of clock model systems. We will therefore exploit the simplicity and reproducibility of fungal and mammalian model systems to cost-effectively address our hypotheses. Due to the conservation of clock architecture, our findings will have the potential to define several novel and unrecognized paradigms in clock regulation over cellular physiology, including the sources and effects of circadian post-transcriptional regulation. These newly defined paradigms will further our long-term goal of elucidating the fundamental principles of circadian timing by identifying the mechanistic underpinnings of circadian control over cellular physiology.

项目摘要/摘要： 昼夜节律是高度保守的、24 小时的振荡，可调节人体生理机能以适应 昼/夜循环，通过确保在生物有利的情况下进行适当的活动来增强健康 次。正常昼夜节律的破坏会对人类的长期医疗前景产生负面影响，使得 了解对人类健康至关重要的细胞生理学昼夜节律调节的机制。 昼夜节律是通过基于转录翻译的负反馈环或时钟来控制的。这 当前生理学昼夜节律调节的范例，称为时钟“输出”，是转录 时钟生成的程序驱动特定时间的基因表达波。然而，我们的研究 揭示了转录编程不能完全解释时钟输出，正如我们发现的弱 随着昼夜节律周期性振荡的 mRNA 和蛋白质之间的相关性，特别是在昼夜节律中 免疫代谢的调节。控制这种转录后调控的机制是 未知，但我们已经证明时钟抑制复合体中的内在蛋白质紊乱可能控制 大分子复合物的形成对转录后时钟输出进行定时。 我们当前的研究目标是确定时钟传递后信息的具体途径。 在生物物理、分子和生理水平上对免疫反应的转录控制。我们 假设昼夜节律转录后代谢调节可以调节免疫组织和性别特异性 通过形成以一天中的时间为中心的大分子蛋白质复合物来调节节律 生物钟的压抑复合体为了检验这个假设，我们将创建一个构象/时间 昼夜节律抑制复合蛋白的 Interactome (CiTI) 图。我们还将调查以下人员的贡献 对免疫细胞功能的性别特异性代谢转录后调节，以证明 基础免疫反应的代谢波动。作为一种保持时间的机制，昼夜节律反馈循环 高度保守，对分子钟的了解大部分来自于研究 时钟模型系统。因此，我们将利用真菌和哺乳动物的简单性和可重复性 模型系统以经济高效地解决我们的假设。由于时钟架构的保护，我们的 研究结果将有可能定义时钟调节中的几种新颖且未被认可的范式 细胞生理学，包括昼夜节律转录后调节的来源和影响。这些新 定义的范式将进一步推进我们阐明昼夜节律基本原理的长期目标 通过确定昼夜节律控制细胞生理学的机制基础。