CAREER: A Systems Biology Approach to Determine How Information from the Cellular Environment is Transduced to the Circadian Clock.

职业：一种系统生物学方法，用于确定来自细胞环境的信息如何转换为昼夜节律时钟。

• 批准号: 2045674
• 负责人: Jennifer Hurley
• 金额: $ 81.76万
• 依托单位: Rensselaer Polytechnic Institute
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2045674&HistoricalAwards=false
• 关键词: CAREER; Systems; Biology; Approach; Determine

This Faculty Early Career Development project will determine the underlying mechanisms that regulate the integration of environmental signals into the circadian clock. Organisms have widely-adapted a highly conserved process to anticipate our 24-hr planetary cycles, termed circadian rhythms, making them a fundamental “rule of life” on planet Earth. Circadian rhythms are controlled by a molecular “clock” that tunes organismal physiology to time a wide variety of cellular functions. Understanding how this clock times physiology is vital as the dysregulation of circadian rhythms can impact a wide array of critical biological functions in most organisms. Though the clock mechanism was presumed to be buffered against changes in an organism’s environment, contemporary research shows that environmental fluctuations can alter circadian regulation at the cellular level through as yet unknown mechanisms and the goals of this research are to identify how environmental signals are incorporated into the circadian timing of a cell. This project will also use the circadian clock to educate future scientists at the college and pre-school levels in the scientific method. As the creation of experimental and computational biological data has surpassed the education of biological researchers in data analytics, the principal investigator will implement a biological data analytics program at the undergraduate level to develop an understanding of how data analytics can solve biological problems. These undergraduate researchers will then work with the Rensselaer Science Ambassadors to reach out to local preschools to teach young children about the scientific method using the growth and tracking of sunflower movements as a model of the circadian clock in an effort to increase STEM interest in underserved communities. The specific objectives of this project are to use computational and molecular approaches to identify and validate the mechanisms by which environmental signals are integrated into the circadian programing of cellular physiology. The molecular clock that drives circadian rhythms has been long believed to be buffered from environmental insult, theoretically acting as a fixed switch that turns a specific set of genes on during the day and off again at night. Contrary to this theory, recent data has shown there is flexibility in circadian regulation, demonstrating that environmental signals can be transduced into the clock’s control of transcript and protein levels. However, there is no mechanistic comprehension of how systemic integration of environmental signals into circadian molecular programing occurs. The data that the investigators have gathered on transcripts and proteins over circadian time from the model organism Neurospora crassa, along with the computational algorithms that they have built to analyze this data, suggest potential mechanisms for the integration of environmental signals into the circadian clock. Therefore, the scientific goals of this proposal are to utilize novel computational approaches to predict specific points at which environmental signals are integrated into circadian transcriptional and translational programming. The investigators will then use this exquisitely tractable circadian model organism to biochemically validate these predictions. This research will contribute to the understanding of how environmental signals are integrated into circadian regulation, which will serve as a model for signal integration in other cellular regulatory systems. This project will also develop novel computational tools with which to study many types of oscillations across research systems. This award was co-funded by the Cellular Dynamics and Function and Systems and Synthetic Biology clusters of the Division of Molecular and Cellular Biosciences.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该教师早期职业发展项目将确定调节环境信号与生物钟整合的基本机制。生物体广泛采用了一种高度保守的过程来预测我们的 24 小时行星周期，称为昼夜节律，使它们成为地球上基本的“生命规则”。昼夜节律由分子“时钟”控制，该分子“时钟”调节生物体生理学以计时多种细胞功能。了解生物钟如何与生理学计时至关重要，因为昼夜节律失调会影响大多数生物体的一系列关键生物功能。尽管生物钟机制被认为可以针对生物体环境的变化进行缓冲，但当代研究表明，环境波动可以通过迄今未知的机制改变细胞水平的昼夜节律调节，这项研究的目标是确定环境信号如何纳入细胞的昼夜节律计时。该项目还将利用生物钟对大学和学前班的未来科学家进行科学方法教育。由于实验和计算生物数据的创建已经超越了生物研究人员在数据分析方面的教育，首席研究员将在本科阶段实施生物数据分析计划，以加深对数据分析如何解决生物问题的理解。然后，这些本科生研究人员将与伦斯勒科学大使合作，深入当地幼儿园，向幼儿传授科学方法，利用向日葵的生长和跟踪作为生物钟的模型，努力提高服务欠缺社区对 STEM 的兴趣。该项目的具体目标是使用计算和分子方法来识别和验证环境信号整合到细胞生理学昼夜节律编程中的机制。长期以来，人们一直认为驱动昼夜节律的分子钟可以缓冲环境的影响，理论上可以充当固定开关，在白天打开一组特定的基因，在晚上再次关闭。与这一理论相反，最近的数据表明昼夜节律调节具有灵活性，证明环境信号可以转化为生物钟对转录物和蛋白质水平的控制。然而，对于如何将环境信号系统性整合到昼夜节律分子编程中，目前还没有机制上的理解。研究人员从模式生物粗糙脉孢菌中收集的昼夜节律转录本和蛋白质数据，以及他们为分析这些数据而构建的计算算法，表明了将环境信号整合到生物钟中的潜在机制。因此，该提案的科学目标是利用新颖的计算方法来预测环境信号整合到昼夜节律转录和翻译编程中的特定点。然后，研究人员将使用这种易于处理的昼夜节律模型生物体来从生化角度验证这些预测。这项研究将有助于理解环境信号如何整合到昼夜节律调节中，这将作为其他细胞调节系统中信号整合的模型。该项目还将开发新颖的计算工具，用于研究跨研究系统的多种类型的振荡。该奖项由分子和细胞生物科学部的细胞动力学、功能与系统和合成生物学集群共同资助。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Circadian regulation of physiology by disordered protein-protein interactions

• DOI: 10.1016/j.sbi.2023.102743
• 发表时间: 2023-12-13
• 期刊: CURRENT OPINION IN STRUCTURAL BIOLOGY
• 影响因子: 6.8
• 作者: Sutton，Lucas B.;Hurley，Jennifer M.
• 通讯作者: Hurley，Jennifer M.