Collaborative Research: MODULUS: A synthetic biology approach to understanding environment sensing in multicellular systems

合作研究：MODULUS：一种理解多细胞系统环境感知的合成生物学方法

• 批准号: 2118037
• 负责人: Andrew Mugler
• 金额: $ 28.5万
• 依托单位: University of Pittsburgh
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2118037&HistoricalAwards=false
• 关键词: Collaborative; Research; MODULUS; synthetic; biology

The goal of this research is to determine how collections of cells, for example, a colony of bacterial cells forming a biofilm, coordinate their behaviors to accomplish goals that are impossible for isolated single cells alone. In particular, the project examines how cellular collectives cooperate to better sense the environment in an effort to determine the spatial location of important resources needed for survival. Computational and experimental methods are integrated in investigations that examine the genetic interactions involved in collective cell sensing. These investigations are used to produce models that advance the understanding of the nature of the cellular interactions. The models are then validated with experimental data. A better understanding of how cells cooperate will inform methods for the construction of synthetic multicellular systems that could be applied to biomanufacturing, environmental remediation or tissue formation for regenerative medicine. In addition to the scientific advances, this project provides societal benefits through curriculum development, the training of students ranging from middle-schoolers to postdoctoral researchers, and the public dissemination of science through mass media.A combination of mathematical modeling and experimental synthetic biology is used to overcome the challenges associated with studying native cell signaling pathways and provide more precise control over genetic and network components. Hypotheses are generated through analytically tractable mathematical models. The resulting predictions are tested on multicellular colonies with realistic, multi-scale agent-based computer models. Next, synthetic gene circuits that contain the proper inter- and intracellular regulatory mechanisms are constructed in Escherichia coli. These gene circuits are then examined experimentally for their collective phenotypes. Finally, the research team fits the mathematical models to the resulting data and validates their predictions on separate sets of experiments. This award was co-funded by the Systems and Synthetic Biology Program in the Division of Molecular and Cellular Biosciences and the Mathematical Biology Program in the Division of Mathematical Sciences.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.

这项研究的目的是确定细胞的集合，例如，形成生物膜的细菌细胞集落，如何协调它们的行为，以实现单独分离的单细胞不可能实现的目标。特别是，该项目研究了细胞集体如何合作，以更好地感知环境，努力确定生存所需的重要资源的空间位置。计算和实验方法被整合在调查中，研究集体细胞传感所涉及的遗传相互作用。这些研究被用来产生模型，促进对细胞相互作用性质的理解。然后用实验数据对模型进行了验证。更好地了解细胞如何合作将为构建合成多细胞系统的方法提供信息，这些系统可应用于生物制造，环境修复或再生医学的组织形成。除了科学进步，该项目还通过课程开发、培训从中学生到博士后研究人员的学生，数学建模和实验合成生物学的结合被用来克服与研究天然细胞信号通路相关的挑战，并提供对遗传和网络的更精确控制。件.假设是通过易于分析的数学模型产生的。由此产生的预测进行了测试，多细胞菌落与现实的，多尺度的基于代理的计算机模型。接下来，在大肠杆菌中构建包含适当的胞间和胞内调节机制的合成基因电路。 这些基因电路，然后检查其集体表型实验。最后，研究小组将数学模型与所得数据拟合，并在单独的实验组中验证他们的预测。该奖项由分子和细胞生物科学部的系统和合成生物学项目以及数学科学部的数学生物学项目共同资助。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。

项目成果

Signaling in microbial communities with open boundaries

• DOI: 10.1016/j.bpj.2023.06.002
• 发表时间: 2023-07-11
• 期刊: BIOPHYSICAL JOURNAL
• 影响因子: 3.4
• 作者: Winkle，James J.;Saha，Soutick;Mugler，Andrew
• 通讯作者: Mugler，Andrew

Cells function as a ternary logic gate to decide migration direction under integrated chemical and fluidic cues.

• DOI: 10.1039/d2lc00807f
• 发表时间: 2023-02-14
• 期刊: Lab on a chip
• 影响因子: 6.1

Multicellular sensing at a feedback-induced critical point

反馈诱导临界点的多细胞传感

• DOI: 10.1103/physreve.102.052411
• 发表时间: 2020
• 期刊: Physical Review E
• 影响因子: 2.4
• 作者: Vennettilli, Michael;Erez, Amir;Mugler, Andrew
• 通讯作者: Mugler, Andrew

Deduction of signaling mechanisms from cellular responses to multiple cues.

• DOI: 10.1038/s41540-022-00262-5
• 发表时间: 2022-11-30
• 期刊: NPJ systems biology and applications
• 影响因子: 4

Signal processing capacity of the cellular sensory machinery regulates the accuracy of chemotaxis under complex cues.

细胞感觉机制的信号处理能力调节复杂线索下趋化性的准确性。

• DOI: 10.1016/j.isci.2021.103242
• 发表时间: 2021-11-19
• 期刊: iScience
• 影响因子: 5.8
• 作者: Moon HR;Saha S;Mugler A;Han B
• 通讯作者: Han B