Understanding the control mechanisms of 3D cell migration from new dimensions

从新维度理解3D细胞迁移的控制机制

• 批准号: 10579538
• 负责人: Bo Sun
• 金额: $ 16.7万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579538
• 关键词: 3-Dimensional; 8 year old; Aging; Area; Award; Cells; Development; Dimensions; Disease Progression; Environment; Epithelial; Equipment; Evolution; Exhibits; Extracellular Matrix; Gene Expression; Goals; Human Biology; Image; Immune System Diseases; Knowledge; Lead; Malignant Neoplasms; Measures; Mechanics; Mesenchymal; Modeling; Molecular; Neoplasm Metastasis; Parents; Pattern; Phenotype; Physiological Processes; Regulation; Research; System; Therapeutic; Time; Tissues; Transforming Growth Factor beta; Transitional Cell; base; cell motility; cell type; crosslink; data quality; fascinate; fluorescence microscope; improved; insight; instrument; mechanical properties; mechanical signal; migration; programs; protein protein interaction; response; tissue regeneration

Cell migration in 3D tissue space is of fundamental importance for human biology. However, predicting and programming 3D cell motility remain as major challenges despite of a firm picture of the molecular machineries involved. To fill the knowledge gap between the overwhelming subcellular details such as protein-protein interactions, and the fascinating dynamic patterns exhibited by different cell types in tissue spaces, I will focus on the mesoscale cellular dynamics, namely the migration phenotype transitions of cells in 3D extracellular matrix (ECM). To advance the goal of the parent award, two specific aims will be pursued within the scope of the parent award. These specific aims rely on access to a dedicated fluorescent microscope with advanced photomanipulation modules. In particular, aim 1 will elucidate how migration phenotype is modulated by the spatial-temporal gradient of ECM mechanical cues. I will measure the migration phenotype transition rates which encode the cellular responses to spatial-temporal gradient of ECM mechanics. The ECM mechanical properties will be controlled in real time by taking advantage of photoactivated ECM crosslinks. The result will lead to the construction of quasipotential energy landscape that quantitatively depict the cell migration phenotype plasticity. In aim 2 I will employ photo convertible fluorescent cell markers to determine the migration phenotype signatures of partial Epithelial-Mesenchymal Transition (EMT) states. I will compare the migration phenotype landscape for epithelial, mesenchymal, and partial EMT cells from the same epithelial spheroid treated by TGF-β. I will also corroborate the findings with underlying gene expression networks, therefore integrating upstream and downstream observations to build mechanistic models that explain the initiation and evolution of cell migration mode plasticity. Both aims are inline with the parent award, while improving data quality and further mechanistic insights. To pursue the aims I will purchase a fluorescent microscope equipped with state-of-the-art imaging and photomanipulation modules. This system will replace an aging 8 years old fluorescent microscope, one of the PI’s main instrument. The acquired equipment will be fully allocated to the project supported by the parent award and the research in this application.

3D组织空间中的细胞迁移对于人类生物学至关重要。但是，预测和 编程3D细胞运动仍然是分子机器牢固图片的主要挑战目的地 涉及。填补压倒性亚细胞细节（例如蛋白质 - 蛋白质）之间的知识差距 相互作用以及组织空间中不同细胞类型暴露的迷人动态模式，我将集中精力 在中尺度细胞动力学上，即3D细胞外基质中细胞的迁移表型转变 （ECM）。为了促进父母奖的目标，将在父母的范围内实现两个具体目标 奖。这些特定的目的依赖于使用高级的专用荧光显微镜的访问 光含量模块。特别是，AIM 1将阐明迁移表型如何由 ECM机械提示的时空梯度。我将衡量迁移表型过渡速率 编码对ECM机制的时空梯度的细胞反应。 ECM机械性能 将利用光活化的ECM交叉链接来实时控制。结果将导致 定量描述细胞迁移表型可塑性的准能量景观的构建。 在AIM 2中，我将使用照片可转换的荧光细胞标记来确定迁移表型特征 部分上皮 - 间质转变（EMT）状态。我将比较迁移表型景观 来自TGF-β处理的同一上皮球形的上皮，间质和部分EMT细胞。我也会 用潜在的基因表达网络证实发现，因此将上游整合 下游观测值以建立机械模型来解释细胞迁移的主动性和演变 模式可塑性。这两个目标都是与父母奖一起融合的，同时提高了数据质量和进一步的机理 见解。要购买目标，我将购买配备了最先进成像的荧光显微镜 光含量模块。该系统将取代8岁老化的荧光显微镜，其中之一 PI的主要乐器。收购的设备将完全分配给由父母奖支持的项目 以及该应用程序中的研究。