Collective Behavior of Cellular Oscillators

从萤火虫的眨眼、蝗虫的行进、鸟类的成群，到组织中细胞的同步行为，都可以在不同的背景下和生物尺度上观察到集体行为。单个细胞有一个生物钟，但它们的同步计时通常只在数千万个细胞的水平上才能观察到。一个巨大的挑战是了解生物体、组织和细胞中的细胞钟如何同步以保持时间。利用一个模型真菌系统，研究人员考虑了关于时钟同步出现的两个主要理论：(1)通过细胞时钟之间共享的生化信号；(2)通过细胞内时钟基因的随机切换。在研究这两种科学理论时，研究人员从单细胞角度探索生物钟的起源，自从诺贝尔奖获得者霍尔、杨和罗斯巴什发现将基因与昼夜节律联系起来以来，这仍然是一个悬而未决的挑战。作为更广泛影响活动的一部分，调查人员为两个REU现场项目开发了生物时钟研究领域的新项目，这两个项目分别是基因组学和计算生物学以及纳米技术和生物医学，这两个项目积极招收克拉克亚特兰大大学的学生。该团队还将组织并参与戈登集体行为会议。为了了解细胞间时钟的同步，有几个挑战需要解决，包括：(1)缺乏有效的随机网络模型来描述细胞时钟群体；(2)缺乏直接测试以询问生化信号作为基于群体感应的同步机制；(3)缺乏关于什么信号(S)同步(S)细胞时钟的知识；(4)缺乏证据来确定时钟基因的随机切换是否在同步中起作用--随机共振(一致性)假说；(5)对时钟在真菌的主要生命阶段--花丝--如何发挥作用缺乏了解。本工作的目的是通过群体感应和随机共振(相干性)两种机制来理解粗毛夜蛾细胞和细丝之间的生物时钟同步。这个跨学科的团队将使用以下方法来研究集体行为的机制：新型微流控平台，用于在受控数量的粗毛裸藻活细胞上测量生物时钟的相位同步；来自统计物理学的方法，用于测试群体感应和随机共振理论框架；以及新开发的连续体内代谢-核磁共振(CIVM-核磁共振)方法，用于识别和表征可能负责时钟同步的信号分子。研究驱动的更广泛的影响活动包括：(1)开发以跨学科研究为中心的课程，时钟协作；(2)开发以生物时钟为中心主题的本科生研究项目，该项目将部署在两个NSF REU站点项目中；以及(3)组织一个集体行为社区，该社区将通过在RIA纽波特举行的新的戈登研究会议参与进来。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Collective behavior can be observed in a variety of contexts and across biological scales, from the blinking of fireflies, the marching of locusts, the flocking of birds, down to the synchronized behavior of cells in tissues. Single cells have a biological clock, but their synchronized timekeeping is usually only observed at the level of tens of millions of cells. A grand challenge is understanding how cellular clocks in organisms, tissues, and cells become synchronized to keep time. Using a model fungal system, Neurospora crassa, investigators consider two principal theories on the emergence of clock synchronization: (1) through a shared biochemical signal between cellular clocks; (2) through the random switching of clock genes within a cell. In examining these two scientific theories, investigators explore the origin of the biological clock from a single cell perspective, which remains an open challenge since the Nobel Prize winning discoveries of Hall, Young, and Rosbash linking genes to circadian rhythms. As part of the Broader Impact activities investigators develop new projects in the area of biological clock research for two REU site programs in Genomics and Computational Biology and Nanotechnology and Biomedicine, which actively recruits students from Clark Atlanta University. The team will also organize and contribute to the Gordon Conference on Collective Behavior (GRC).In order to understand the synchronization of clocks between cells, there are several challenges that need to be addressed, including: (1) lack of working stochastic network models to describe populations of cellular clocks; (2) lack of a direct test for interrogating the biochemical signals as quorum sensing based synchronization mechanisms; (3) lack of knowledge on what signal(s) synchronize(s) cellular clocks; (4) lack of evidence to determine whether or not stochastic switching in clock genes plays a role in synchronization – the stochastic resonance (coherence) hypotheses; (5) lack of understanding how the clock functions at the predominant life stage of fungi, the filament. The goal of this work is to understand the synchronization of biological clocks between cells and filaments in N. crassa by two mechanisms, quorum sensing vs. Stochastic Resonance (Coherence). The interdisciplinary team will investigate mechanisms of collective behavior using: novel microfluidics platforms to measure phase synchronization of biological clocks on a controlled number of living N. crassa cells, methods from Statistical Physics to test quorum sensing versus Stochastic Resonance theoretical frameworks, and a newly developed Continuous in vivo metabolism-NMR (CIVM-NMR) method to identify and characterize signaling molecules that may be responsible for clock synchronization. The research-driven Broader Impact activities include: (1) Development of interdisciplinary research-centered course, Clock Collaboratorium; (2) Development of undergraduate research projects focused on the central theme of the biological clock, which will be deployed in two NSF REU site programs; and (3) Organization of a collective behavior community that will engage through a new Gordon Research Conference in Newport, RI.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.