CAREER: Molecular and Cellular Mechanisms Underlying Circuit-Host Interactions

职业：电路-宿主相互作用的分子和细胞机制

• 批准号: 2143229
• 负责人: Xiaojun Tian
• 金额: $ 68.77万
• 依托单位: Arizona State University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2143229&HistoricalAwards=false
• 关键词: CAREER; Molecular; Cellular; Mechanisms; Underlying

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2).Synthetic gene circuits are engineered circuits that allow researchers to program and design cells for a variety of biotechnology applications, including the synthesis of therapeutics, sustainable agriculture and production of renewable resources. Although many synthetic genetic circuits have been successfully used, they have a high rate of failure due in part to negative impacts on host cells. The long-term goals of this project are to better understand how synthetic circuit design impacts host cells and to use this knowledge to design circuits that are less harmful. A diverse group of high school, undergraduate, and graduate students will participate in the research project through active learning and hands-on training. American Rescue Plan funding of this project will support this researcher at a critical stage in his career.Synthetic gene circuits over the last two decades have shown remarkable functional versatility in engineering host organisms and cellular capabilities for desired functions. However, most synthetic gene circuits are highly dependent on multiple undesired factors through complicated circuit-host interactions, such as metabolic burden, cell growth feedback, and resource competition. Another critical reason is that the fundamental molecular mechanism the host cells could adopt to entertain and constrain exogenous synthetic gene circuits is still unclear. Moreover, the lack of quantitative tools to accurately predict the behavior of gene circuits and control their interactions with the host cell is impeding progress in the field. This research program aims to dissect the fundamental mechanisms of circuit-host interactions to understand the molecular and cellular organization of the host system and engineer predictable/controllable gene circuits. A library of gene circuits will be built to gain in-depth mechanistic understandings of how circuit-host interactions are established. An ensemble of mathematical models at different levels will be formulated to characterize the host-circuit mutual interactions at single-cell, population, or ecological levels. The proposed research will advance the quantitative understanding of the crosstalk between gene circuits and bacterial physiology, develop a quantitative characterizing of complex circuit-host interactions on the host cell function and behavior of engineered gene circuits, and facilitate gene circuit design to meet design specifications through practical strategies that target the circuit-host interactions.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.

该奖项全部或部分由《2021年美国救援计划法案》（公法117-2）资助。合成基因电路是一种工程电路，它允许研究人员为各种生物技术应用编程和设计细胞，包括治疗药物的合成，可持续农业和可再生资源的生产。尽管许多合成遗传电路已经成功使用，但由于对宿主细胞的负面影响，它们的失败率很高。该项目的长期目标是更好地了解合成电路设计如何影响宿主细胞，并利用这些知识来设计危害较小的电路。高中生、本科生和研究生将通过积极学习和实践培训参与研究项目。美国救援计划对该项目的资助将支持该研究人员在其职业生涯的关键阶段。在过去的二十年中，合成基因电路在工程宿主生物和细胞功能方面显示出显着的功能多功能性。然而，大多数合成基因回路高度依赖于多种不希望的因素，如代谢负担、细胞生长反馈和资源竞争等，通过复杂的回路-宿主相互作用。另一个重要的原因是宿主细胞接受和抑制外源合成基因回路的基本分子机制尚不清楚。此外，缺乏定量工具来准确预测基因回路的行为并控制它们与宿主细胞的相互作用，这阻碍了该领域的进展。本研究计划旨在剖析电路-宿主相互作用的基本机制，以了解宿主系统的分子和细胞组织，并设计可预测/可控的基因电路。将建立一个基因电路库，以深入了解电路-宿主相互作用是如何建立的。在不同水平的数学模型的集合将制定表征宿主电路相互作用在单细胞，种群，或生态水平。本研究将促进对基因电路与细菌生理之间串扰的定量理解，对复杂的电路-宿主相互作用对宿主细胞功能和工程基因电路行为的定量表征，并通过针对电路-宿主相互作用的实用策略促进基因电路设计满足设计规范。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

Growth feedback confers cooperativity in resource-competing synthetic gene circuits

• DOI: 10.1016/j.chaos.2023.113713
• 发表时间: 2023-06-24
• 期刊: CHAOS SOLITONS & FRACTALS
• 影响因子: 7.8
• 作者: Melendez-Alvarez，Juan Ramon;Zhang，Rong;Tian，Xiao-Jun
• 通讯作者: Tian，Xiao-Jun

Effects of growth feedback on gene circuits: A dynamical understanding

• DOI: 10.1101/2023.06.06.543915
• 发表时间: 2023-06
• 期刊: bioRxiv
• 作者: Ling-Wei Kong;Wenjia Shi;Xiao-Jun Tian;Ying-Cheng Lai