Bilateral BBSRC-NSF/BIO: Asymmetric division and the temporal dynamics of cell motility

双边 BBSRC-NSF/BIO：不对称分裂和细胞运动的时间动态

• 批准号: 1758081
• 负责人: Katie Bentley
• 金额: $ 15.12万
• 依托单位: Trustees of Boston University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1758081&HistoricalAwards=false
• 关键词: Bilateral; BBSRC; NSF; BIO; Asymmetric

This collaborative project between researchers in the US (Beth Israel Deaconess Medical Center) and the UK (University of Manchester) aims to define the fundamental mechanisms controlling cell migration during organ development. In growing tissues, cells usually divide symmetrically to produce two identical daughter cells. However, in some instances cell divisions are asymmetric and give rise to intrinsically distinct daughters that have different characteristics including the ability to move (or motility). This project will explore the molecular and cellular basis of post-cell division asymmetry in cell motility and define the functional role of asymmetric divisions in the control of cell migration during tissue growth. Not only will this research generate freely available novel computational methods and analysis tools suitable for a wide array of applications, the findings of this work will have wide-reaching implications for understanding the control of cell migration across a plethora of cellular systems and organisms. Through its broader impacts, the project will additionally expose undergraduate and high school students (with emphasis on recruiting underrepresented groups) to integrated cross-disciplinary computational / experimental scientific approaches and provide hands-on experience of international collaborative research techniques upon the creation of several new, targeted, interactive Global Interface Science (GIS) workshops. Moreover, guidance on implementing similar GIS workshops anywhere worldwide will be widely disseminated via online media. Asymmetric cell division (ACD) specifies differential daughter cell fates in many systems, but has never before been implicated in determining the temporal dynamics of cell motility. This project will define how ACD acts as a novel symmetry-breaking mechanism to ensure daughter cells acquire distinct motilities during tissue growth. An integrated in silico and in vivo approach will be taken, innovating a novel multiscale hybrid, spatiotemporal agent-based model (ABM) that will inform single-cell live imaging experiments of endothelial cells in zebrafish embryos. These studies will probe ACD in motile cells, validate model predictions and altogether elucidate a previously unexplored role for mitosis in the control of migration. In particular, the interplay of ACD with cell signaling, geometry and mechanical motility cues across different scales, from the molecular to the cellular will be investigated through the following tasks: A) develop new modeling methodologies to investigate the role of localized intracellular dynamics in the establishment of asymmetric post-mitotic motility and functionally validate model predictions at sub-cellular resolution in vivo; B) Predict the effects of ACD-driven differences in cell architecture on motility dynamics in silico alongside quantification of dynamic alterations in cell architecture occurring during division in vivo; C) quantify pre- and post-mitotic fluctuations in cell tension at single-cell resolution in vivo and define the interplay of cell tension with the induction of ACD and differential motility in silico and in vivo. The products of this research will include novel computational ABM models and image analysis software, which will uniquely enable studies of key aspects of cell migration and will be made freely available to the wider scientific community. In additional broader impacts, the PIs will organize international workshops to provide a platform for promoting the widespread use of similar integrated in silico / in vivo approaches in studies of tissue morphogenesis across diverse cellular systems and organisms.This collaborative US/UK project is supported by the US National Science Foundation and the UK Biotechnology and Biological Sciences Research Council. Within NSF, the award is cofunded by the Division of Molecular And Cellular Biosciences and the Division of Chemical, Bioengineering, Environmental and Transport Systems.

美国（以色列贝丝以色列执事医疗中心）和英国（曼彻斯特大学）的研究人员之间的合作项目旨在定义控制器官开发过程中控制细胞迁移的基本机制。在生长的组织中，细胞通常对称地分裂以产生两个相同的子细胞。但是，在某些情况下，细胞分裂是不对称的，并引起本质上不同的女儿，这些女儿具有不同的特征，包括移动能力（或运动能力）。 该项目将探索细胞运动后细胞分裂不对称性的分子和细胞基础，并定义不对称分裂在组织生长过程中细胞迁移控制中的功能作用。这项研究不仅会生成可免费获得的新型计算方法和分析工具，适合各种应用程序，而且这项工作的发现将具有广泛的意义，以理解跨大量细胞系统和生物体的细胞迁移的控制。通过其更广泛的影响，该项目将额外揭示本科生和高中生（重点招募代表性不足的群体），以综合跨学科计算 /实验性科学方法，并提供国际协作研究技术的动手经验，以创建一些新的，有针对性的，有针对性的，有针对性的，有针对性的，有针对性的，互动的全球界面科学（GIS）。此外，全世界在全球任何地方实施类似GIS研讨会的指南将通过在线媒体广泛传播。非对称细胞分裂（ACD）指定了许多系统中的差异子细胞命运，但从未与确定细胞运动的时间动力学有关。该项目将定义ACD如何充当一种新型的破坏对称性机制，以确保子细胞在组织生长过程中获得独特的运动。将采用一种集成的硅和体内方法，创新了一种新型的多尺度混合，基于时空的代理模型（ABM），该模型（ABM）将为斑马鱼胚胎中内皮细胞的单细胞实时成像实验提供信息。这些研究将在运动细胞中探测ACD，验证模型预测，并完全阐明先前未开发的有丝分裂在迁移控制中的作用。特别是，将通过以下任务研究ACD与细胞信号传导，几何学和机械运动性线索的相互作用，从分子到细胞，将研究： b）预测细胞结构中ACD驱动的差异对计算机运动动力学的影响，同时量化了体内分裂期间细胞结构的动态变化； c）在体内单细胞分辨率下量化细胞张力的有丝分裂前和后的波动，并定义了细胞张力与硅和体内ACD诱导和差异运动的相互作用。这项研究的产品将包括新颖的计算ABM模型和图像分析软件，该软件将独特地研究细胞迁移的关键方面，并将自由地提供给更广泛的科学界。在其他更广泛的影响下，PIS将组织国际研讨会，以提供一个平台，以促进在各种细胞系统和生物体跨组织形态发生的研究中广泛使用类似集成的类似使用，这是美国国家科学基金会和英国生物技术和生物学研究委员会的支持。 在NSF内部，该奖项由分子和细胞生物科学的划分以及化学，生物工程，环境和运输系统的分配。