Collective Behavior of Cellular Oscillators

细胞振荡器的集体行为

• 批准号: 2041546
• 负责人: Jonathan Arnold
• 金额: $ 80.72万
• 依托单位: University of Georgia Research Foundation Inc
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2041546&HistoricalAwards=false
• 关键词: Collective; Behavior; Cellular; Oscillators

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.

集体行为可以在各种环境和生物尺度上观察到，从萤火虫的眨眼，蝗虫的行军，鸟类的成群结队，到组织中细胞的同步行为。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细胞的水平上被观察到。一个巨大的挑战是理解生物体、组织和细胞中的细胞时钟是如何同步以保持时间的。利用一种模型真菌系统——粗神经孢子虫，研究人员考虑了时钟同步出现的两种主要理论：(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，研究人员从单细胞的角度探索了生物钟的起源，自诺贝尔奖得主霍尔、杨和罗斯巴什发现基因与昼夜节律联系起来以来，这仍然是一个公开的挑战。作为“更广泛影响”活动的一部分，研究人员在基因组学和计算生物学以及纳米技术和生物医学两个REU站点项目中开发了生物钟研究领域的新项目，这些项目积极招募来自克拉克亚特兰大大学的学生。该团队还将组织并为戈登集体行为会议（GRC）做出贡献。为了理解细胞间时钟的同步，有几个挑战需要解决，包括：(1)缺乏工作的随机网络模型来描述细胞时钟群；(2)缺乏对生物化学信号作为群体感应同步机制的直接检验；(3)不知道什么信号能同步细胞时钟；(4)缺乏证据来确定时钟基因的随机开关是否在同步中起作用-随机共振（相干）假说；(5)缺乏对真菌的主要生命阶段——菌丝的生物钟功能的了解。本研究的目的是通过群体感应与随机共振（Coherence）两种机制来了解草属植物细胞和细丝之间的生物钟同步。跨学科团队将使用以下方法研究集体行为的机制：新的微流控平台，以测量控制数量的活N.草细胞上的生物钟相位同步，从统计物理学中测试群体感应与随机共振理论框架的方法，以及新开发的连续体内代谢核磁共振（CIVM-NMR）方法，以识别和表征可能负责时钟同步的信号分子。研究驱动的广泛影响活动包括：(1)以跨学科研究为中心的课程开发，时钟合作；(2)开展以生物钟为中心主题的本科研究项目，并将在2个NSF REU站点项目中部署；(3)组织一个集体行为社区，该社区将通过在罗德岛新港举行的新戈登研究会议参与。该奖项反映了美国国家科学基金会的法定使命，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。

项目成果

MICROFLUIDIC CHAMBER DEVICE TO TEST QUORUM SENSING THEORY

用于测试群体感应理论的微流控室装置

• 发表时间: 2020
• 期刊: The 24th International Conference on Miniaturized Systems for Chemistry and Life Sciences (µTAS 2020
• 作者: Cheong J, Qiu X

Quorum sensing in single cells of Neurospora crassa

粗糙脉孢菌单细胞的群体感应

• 发表时间: 2021
• 期刊: MicroTAS2021
• 作者: Qiu, X.

Measuring how clocks in single cells of Neurospora crassa communicate in microfluidic devices

测量粗糙脉孢菌单细胞中的时钟如何在微流体装置中通信

• 发表时间: 2021
• 期刊: MicroTAS 2021
• 作者: Cheong, J. H.

Ensemble Methods for Identifying RNA Operons and Regulons in the Clock Network of Neurospora Crassa

• DOI: 10.1109/access.2022.3160481
• 发表时间: 2022-01-01
• 期刊: IEEE ACCESS
• 影响因子: 3.9
• 作者: Al-Omari，Ahmad M.;Griffith，James;Arnold，Jonathan
• 通讯作者: Arnold，Jonathan