CAREER: Deciphering Design Principles of Early Embryonic Cell Cycles

生物钟是由基因控制的过程，它使生物体能够预测环境变化，这是发育生物学的核心。该项目将开发一个合成生物学框架来揭示时钟周期的定量信息以及这个周期如何影响细胞结构。该项目将使用这一框架来解决如何设计有丝分裂时钟来实现年轻胚胎斑马鱼细胞的稳健细胞周期。鉴于生物钟在从细菌到人类的生物体中无处不在，这个项目将为发育生物学和包括癌症在内的疾病提供见解。这项高度跨学科的研究将为K-12，本科生和研究生提供培训资源，以获得理论建模，光学成像，纳米制造，发育生物学，数据分析和科学交流方面的经验。推广活动将包括与当地专业教育工作者合作开发的博物馆演示和实验室开放日。该项目的目标是建立一种合成生物学方法来破译驱动斑马鱼胚胎早期细胞周期的有丝分裂回路的基本设计原理。该项目将开发一个无细胞系统，构建人工细胞来重建类似于早期胚胎细胞分裂过程的有丝分裂事件，并开发新的单细胞成像和跟踪系统。无细胞系统的结果将在活胚胎中进行测试，以评估其生物学相关性。本项目的目标是：1)建立计算方法并寻找所有鲁棒性和可调振荡拓扑结构；2)人工构建有丝分裂细胞并检查其拓扑结构的鲁棒性和可调性功能；3)结合体外和体内研究来评估有丝分裂时钟在活斑马鱼胚胎中的作用。这一发现可以推广到与有丝分裂钟具有相似核心结构的广泛的生物钟。

Biological clocks are genetically controlled processes that allow organisms to anticipate environmental changes, which are central to developmental biology. This project will develop a synthetic biology framework to reveal quantitative information on clock cycles and how this cycle influences cellular architecture. The project will use this framework to address how the mitotic clock is designed to achieve robust cell cycles in young embryonic zebrafish cells. Given that biological clocks exist ubiquitously in organisms from bacteria to humans this project will provide insights into developmental biology and diseases, including cancer. This highly interdisciplinary research will serve as a training resource for K-12, undergraduate and graduate students to gain experience in theoretical modeling, optical imaging, nanofabrication, developmental biology, data analysis and scientific communication. Outreach activities will include demonstrations at museums and lab open days developed in collaboration with local professional educators.The goal of this project is to establish a synthetic biology approach to decipher the fundamental design principles of a mitotic circuit that drives early cell cycles in zebrafish embryos. This project will develop a cell-free system, build artificial cells to reconstitute mitotic events that resemble the processes of early embryonic cell divisions, and develop novel single-cell imaging and tracking systems. The results in the cell-free system will be tested in live embryos to assess their biological relevance. The objectives of this project are to: 1) establish computational methods and search for all robust and tunable oscillation topologies, 2) artificially construct mitotic cells and examine its topology for functions of robustness and tunability, and 3) combine in vitro and in vivo studies to evaluate the role of mitotic clocks in live zebrafish embryos. The findings may be generalizable to a wide spectrum of biological clocks that share similar core architecture with the mitotic clock.