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

这个教师早期职业发展项目将确定调节环境信号整合到生物钟的潜在机制。生物体已经广泛适应了一个高度保守的过程，以预测我们的24小时行星周期，称为昼夜节律，使其成为地球上的基本“生命规则”。昼夜节律是由一个分子“时钟”控制的，它调节生物体的生理机能，为各种细胞功能计时。了解这种生物钟是如何计时生理的是至关重要的，因为昼夜节律的失调会影响大多数生物体中广泛的关键生物功能。虽然生物钟机制被认为是对生物体环境变化的缓冲，但当代研究表明，环境波动可以通过未知的机制在细胞水平上改变昼夜节律调节，本研究的目标是确定环境信号如何被纳入细胞的昼夜节律定时。该项目还将使用生物钟来教育未来的科学家在大学和学前水平的科学方法。由于实验和计算生物数据的创建已经超过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，以了解数据分析如何解决生物问题。然后，这些本科生研究人员将与伦斯勒科学大使合作，接触当地的幼儿园，利用向日葵运动的生长和跟踪作为生物钟的模型，向幼儿传授科学方法，以提高服务不足社区的STEM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的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伤害，理论上它就像一个固定的开关，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，表明环境信号可以被转换为生物钟对转录本和蛋白质水平的控制。然而，没有机制的理解如何系统整合的环境信号到昼夜节律的分子编程发生。研究人员从模式生物粗糙脉孢菌（Neurospora crassa）中收集的关于昼夜节律时间的转录本和蛋白质的数据，沿着他们为分析这些数据而建立的计算算法，表明了环境信号整合到昼夜节律钟中的潜在机制。因此，该提案的科学目标是利用新的计算方法来预测环境信号整合到昼夜转录和翻译编程中的特定点。然后，研究人员将使用这种精致易处理的昼夜节律模式生物来生物化学地验证这些预测。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。该项目还将开发新的计算工具，用于研究跨研究系统的许多类型的振荡。该奖项由分子和细胞生物科学部的细胞动力学和功能以及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知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.