Science and Technology Center for Quantitative Cell Biology

定量细胞生物学科技中心

• 批准号: 2243257
• 负责人: Zaida Luthey-Schulten
• 金额: $ 2978.11万
• 依托单位: University of Illinois at Urbana-Champaign
• 依托单位国家: 美国
• 项目类别: Cooperative Agreement
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-08-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2243257&HistoricalAwards=false
• 关键词: Science; Technology; Center; Quantitative; Cell

The Science and Technology Center for Quantitative Cell Biology (QCB) aims to revolutionize our understanding of cells via the creation of whole-cell models that faithfully capture all aspects of cell function and emergent behavior. QCB will leverage the newest advances in computing, artificial intelligence, and super-resolution imaging, as well as the state of the art -omics and cellular measurements, to develop models with novel details and predictive capabilities. Ultimately, QCB aspires to unlock the secrets of living cells, to predict normal and abnormal cellular functions, and to design single cells and multicellular systems that provide solutions for human health, climate change and agriculture, fueling the U.S. bioeconomy. QCB’s education, broadening participation, and knowledge sharing programs will ensure that a diverse workforce is well-trained in quantitative cell biology. The goal of this center is to bring together a community of experimentalists who will study key “modules” of the cell with a community of computational scientists who will build a unified model of the cell, comprising all fundamental processes, including gene expression, metabolism, and division, for both eukaryotic and bacterial cells under the influence of their environment. Unified models have the potential to make predictions of the time-dependent behavior for every modeled biochemical species – a quantity of data akin to performing hundreds of simultaneous experiments. The time is ripe for attempting a synthesis of the comprehensive knowledge we have from molecular biology, chemistry, and physics into a complete model of the cell. On the technology side, the University of Illinois at Urbana-Champaign has a strong history of tracking single molecules, and is a collaborative adopter of a facility that uses minimal photon fluxes (MINFLUX) microscopy to locate biomolecules to 2 nanometer spatial resolution and track them with 100 microsecond time resolution within the context of a living cell. MINFLUX represents a 10-fold improvement over all other existing single-molecule techniques, making the dynamical connection with structural electron microscopy and IR metabolomics techniques. On the cell biology side, examples of “modules” of the cell are molecular motors as they transport cargo across the cell, formation of spliceosomes through assembly of RNA-protein transcriptional complexes within the nucleus, chromosome dynamics and interactions with nuclear condensates during gene expression, changes in organelle networks as they transition from healthy and to unhealthy states, and interactions of eukaryotic and bacterial cells and their organelle networks. These cellular dynamical processes studied by MINFLUX will be complemented by cryogenic electron microscopy (CEM) measurements of large functional intermediates/complexes, and molecular dynamics and coarse-grained simulations to determine essential mechanistic states. Dynamical infrared microscopy will focus on the often-neglected small metabolites inside cells. Regions of the entire cell captured by cryogenic electron tomography (CET) will serve as the basis for the ultrastructure in cell simulations, with resolutions ranging from 8-32 nanometers in space and 50-100 microsecond time steps. Cell simulations of the reaction-diffusion processes will integrate metabolic kinetics with the dynamics of genetic information processes obtained from MINFLUX measurements to create a unified model of cellular function, from the molecular level up to cell division.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.

定量细胞生物学科学和技术中心(QCB)旨在通过创建完整的细胞模型来彻底改变我们对细胞的理解，该模型能够忠实地捕捉细胞功能和新出现的行为的所有方面。QCB将利用计算、人工智能和超分辨率成像方面的最新进展，以及最先进的组学和细胞测量技术，开发具有新颖细节和预测能力的模型。最终，QCB渴望解开活细胞的秘密，预测正常和异常的细胞功能，并设计单细胞和多细胞系统，为人类健康、气候变化和农业提供解决方案，推动美国生物经济。QCB的教育、扩大参与和知识共享计划将确保一支多元化的劳动力队伍在定量细胞生物学方面受到良好培训。该中心的目标是将一个研究细胞关键模块的实验者社区与一个计算科学家社区聚集在一起，计算科学家社区将建立一个统一的细胞模型，包括真核细胞和细菌细胞在环境影响下的所有基本过程，包括基因表达、新陈代谢和分裂。统一的模型有可能对每个建模的生化物种的依赖时间的行为做出预测--数据量类似于执行数百个同时进行的实验。现在是时候尝试把我们从分子生物学、化学和物理学所拥有的全面知识合成成一个完整的细胞模型了。在技术方面，伊利诺伊大学厄巴纳-香槟分校在跟踪单分子方面有很强的历史，并且合作采用了一种设备，该设备使用最小光子通量(MINFLUX)显微镜来定位2纳米空间分辨率的生物分子，并在活细胞的背景下以100微秒的时间分辨率跟踪它们。MINFLUX比所有其他现有的单分子技术提高了10倍，使其与结构电子显微镜和红外代谢组学技术动态联系在一起。在细胞生物学方面，细胞的“模块”的例子包括在细胞内运送货物的分子马达，通过在细胞核内组装RNA-蛋白质转录复合体形成剪接体，染色体动力学以及在基因表达期间与核凝聚体的相互作用，细胞器网络从健康状态和不健康状态转变时的变化，以及真核细胞和细菌细胞及其细胞器网络的相互作用。MINFLUX研究的这些细胞动力学过程将得到大型功能中间体/复合体的低温电子显微镜(CEM)测量以及分子动力学和粗粒度模拟的补充，以确定基本的机械状态。动态红外显微镜将聚焦于细胞内经常被忽视的小代谢物。低温电子断层扫描(CET)捕捉到的整个细胞的区域将作为细胞模拟的超微结构的基础，空间分辨率从8-32纳米，时间步长从50-100微秒。反应-扩散过程的细胞模拟将把代谢动力学与从MINFLUX测量获得的遗传信息过程的动力学结合起来，以创建从分子水平到细胞分裂的细胞功能的统一模型。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。