Technical Development Unit 1: Intelligent live imaging of metastasis patterns and subcellular molecular states at the whole organism level

技术开发单元1：整个生物体水平的转移模式和亚细胞分子状态的智能实时成像

• 批准号: 10491347
• 负责人: Reto Paul Fiolka
• 金额: $ 25.65万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-24 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10491347
• 关键词: 3-Dimensional; Anatomy; Animal Model; Animals; Atlases; Automobile Driving; Behavior; Behavioral; Biological Assay; Cell physiology; Cells; Characteristics; Detection; Development; Disease; Embryo; Environmental Risk Factor; Evolution; Fluorescence Microscopy; Genomics; Heterogeneity; Human; Image; In Situ; Individual; Intelligence; Lasers; Light; Lighting; Machine Learning; Malignant Neoplasms; Maps; Microscope; Microscopy; Molecular; Molecular Probes; Monitor; Morphology; Multimodal Imaging; Neoplasm Metastasis; Optics; Organism; Pathway interactions; Pattern; Phase; Phenotype; Population; Process; Property; Resolution; Signal Transduction; Site; Source; Spottings; Stretching; System; Systems Analysis; Technology; Time; Tissues; Variant; Visualization; Whole Organism; Xenograft Model; Xenograft procedure; Zebrafish; adaptive optics; analysis pipeline; arm; base; cancer cell; cell behavior; cell type; cellular imaging; computational pipelines; fluorescence imaging; functional plasticity; high resolution imaging; imaging capabilities; multimodality; next generation sequencing; non-genomic; novel; optogenetics; prevent; programs; single cell sequencing; software development; submicron; technology development; transcriptomics; tumor; tumor xenograft

Project Summary Fluorescence microscopy combined with the optically transparent Zebrafish xenograft model has the potential to unravel the functional heterogeneity and adaptation of cancer cells that underlies their metastatic potential. However, this requires bridging disparate scales, as metastatic sites can form across an entire organism, and cancer cells within need to be imaged with sub-micron 3D resolution. Further, low occupancy of specific metastatic niches requires imaging many xenografts. This stretches the capabilities of current microscope technology as they fail to provide high-throughput, high-spatial resolution, and whole organism imaging capability at the same time. To break through this boundary, we will develop a new multi-modal microscope to autonomously image both at the organism and subcellular scale in a high-throughput fashion. An optogenetic module further allows to manipulate pathways or photo-convert selected cancer cells for either tracking or single cell sequencing approaches. A computational pipeline will automatically detect and select recurring metastatic sites across many xenografts for high-resolution imaging. This will allow for the first time the quantitative comparison of functional states such as morphology, survival and proliferation, and signaling between different niches. We anticipate that the combination of multi-modal microscopy and the computational pipelines for autonomous imaging will shed new light on key aspects of functional heterogeneity in cancer metastasis.

项目概要 荧光显微镜与光学透明斑马鱼异种移植模型相结合具有潜力 揭示癌细胞转移潜力的功能异质性和适应性。 然而，这需要桥接不同的尺度，因为转移位点可以在整个生物体中形成，并且 内部的癌细胞需要以亚微米 3D 分辨率成像。此外，特定场所的占用率较低 转移性微环境需要对许多异种移植物进行成像。这扩展了当前显微镜的功能 技术，因为它们无法提供高通量、高空间分辨率和整个生物体成像 同时具备能力。为了突破这一界限，我们将开发一种新型多模态显微镜 以高通量方式在生物体和亚细胞尺度上自主成像。光遗传学 模块还允许操纵路径或对选定的癌细胞进行光转换，以进行跟踪或 单细胞测序方法。计算管道将自动检测并选择重复出现的 许多异种移植物的转移位点进行高分辨率成像。这将首次允许 形态、存活和增殖以及信号传导等功能状态的定量比较 不同利基之间。我们预计多模态显微镜和计算技术的结合 自主成像管道将为癌症功能异质性的关键方面提供新的线索 转移。