Northwestern University Center for Chromatin NanoImaging in Cancer (NU-CCNIC)

西北大学癌症染色质纳米成像中心 (NU-CCNIC)

• 批准号: 10539321
• 负责人: Vadim Backman
• 金额: $ 166.3万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-10 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10539321
• 关键词: 3-Dimensional; Address; Aftercare; Biological Assay; Cancer Biology; Cell Nucleus; Cell physiology; Cells; Chromatin; Chromatin Structure; Complex; Computing Methodologies; Cytotoxic Chemotherapy; DNA; Data; Data Set; Development; Diameter; Disease remission; Disparate; Electron Microscopy; Epigenetic Process; Event; Feedback; Fostering; Future; Genes; Genetic; Genetic Transcription; Genome Mappings; Genomics; Growth; Heterogeneity; Image; Imaging Techniques; Imaging technology; Knowledge; Label; Length; Link; Malignant Neoplasms; Methods; Microscopy; Mission; Molecular; Molecular Conformation; Molecular Target; Nanoscopy; Oncology; Optics; Pathway interactions; Pattern; Physics; Play; Population; Process; Relapse; Research; Resistance; Resistance development; Resolution; Role; Scanning; Series; Solid; Stem Cell Research; Techniques; Technology; Testing; Therapeutic; Time; Translating; Transmission Electron Microscopy; Universities; Vision; Visualization; anti-cancer therapeutic; anticancer research; cancer cell; cancer stem cell; cellular imaging; chemotherapy; data modeling; electron tomography; epigenomics; follow-up; frontier; imaging capabilities; imaging platform; insight; live cell microscopy; molecular imaging; molecular modeling; molecular scale; nanoimaging; nanoscale; nanosensors; new technology; novel therapeutic intervention; novel therapeutics; pressure; prevent; programs; quantitative imaging; single molecule; spatiotemporal; stem; stem cell biology; stressor; technology development; temporal measurement; therapeutically effective; therapy resistant; three dimensional structure; transcriptional reprogramming; tumor; tumor progression; ultra high resolution

Overall: PROJECT SUMMARY Cancer stem cells (CSCs) play a critical role in fostering tumor resistance to therapies and relapse after treatment. This presents a crucial barrier to the development of successful anti-cancer therapeutics. Transcriptional reprogramming and plasticity play a critical role in and out of the CSC state, which in turn are interdependent on the regulatory function of the three-dimensional (3D) structure of chromatin, epigenetic states, and other molecular events. Our understanding of fundamental CSC biology has been hampered by the need for cellular nanoscale imaging technologies that provide both highly detailed structural information regarding 3D chromatin organization and highly multiplexed molecular imaging of the many molecular regulators and events involved in CSC processes. We propose to establish the Northwestern University Center for Chromatin Nanoimaging in Cancer (NU-CCNIC) to address this fundamental technology gap in cellular nanoscale imaging and deploy the new technologies to address the fundamental knowledge gap in CSC biology. The Center converges experts in cellular nanoscale imaging, computational imaging, molecular modeling, computational genomics, CSC biology, and oncology. The Center will develop, test, validate, iterate, and deploy an integrated and co-registered Multi-scale Chromatin Nanoimaging Platform that will comprise three “nested-doll” imaging techniques: chromatin scanning transmission electron microscopy, optical spectroscopic super-resolution nanoscopy, and optical spectroscopic nanosensing. The Nanoimaging Platform will enable quantitative imaging of chromatin structure and highly multiplexed molecular and gene-specific localization, at the most fundamental length-scale approaching 1 nm resolution, including the imaging of statistically significant cell populations and live cells with high temporal resolution over prolonged temporal follow-up times. The Nanoimaging Platform will be bridged to computational genomics, epigenomics, genome mapping, and predictive transcriptional modeling datasets. These technologies will be deployed to answer several long-standing open questions in CSC biology. We will elucidate whether CSCs can originate from non-CSCs via transcriptional reprogramming, test the role of chromatin structure in fostering transcriptional plasticity in CSC processes, and explore the possibility of transcriptionally reprogramming CSCs to exit the stem-state as a new therapeutic strategy. All aspects of the technology development will be guided by the needs of the CSC biology testbed through a series of research feedback loops. In the long term, such single-cell nanoimaging technologies will help comprehensive understanding of the complex interplay between structural, physico-chemical, and molecular genomic events. We anticipate that these convergence studies will provide new insights into CSC biology, which are impossible to reveal with the use of any single method, and open new opportunities for identifying therapeutic strategies.

总体情况：项目总结 肿瘤干细胞(CSCs)在培养肿瘤对治疗的抵抗力和术后复发方面起着关键作用 治疗。这对成功的抗癌疗法的发展是一个关键的障碍。 转录重编程和可塑性在CSC状态和CSC状态之外都起着关键作用，而CSC状态又是 依赖染色质的三维(3D)结构的调节功能，表观遗传状态， 以及其他分子事件。我们对基础CSC生物学的理解因需要而受到阻碍 用于细胞纳米成像技术，该技术提供关于3D的高度详细的结构信息 染色质组织和许多分子调节因子和事件的高度多元化的分子成像 参与CSC流程。我们建议建立西北大学染色质研究中心 肿瘤纳米成像(NU-CCNIC)，以解决细胞纳米成像中的这一基本技术差距 并部署新技术来解决CSC生物学中的基本知识差距。《中心》 汇聚细胞纳米成像、计算成像、分子建模、计算 基因组学、CSC生物学和肿瘤学。该中心将开发、测试、验证、迭代和部署集成的 和共同注册的多尺度染色质纳米成像平台，将组成三个“嵌套娃娃”成像 技术：染色质扫描电子显微镜、光学光谱超分辨 纳米显微镜和光学光谱纳米传感。纳米成像平台将实现定量成像 染色质结构和高度多元化的分子和基因特异性定位，最根本的 接近1纳米分辨率的长度尺度，包括对具有统计意义的细胞群体和 在延长的时间跟踪时间内，具有高时间分辨率的活细胞。纳米成像平台将 连接到计算基因组学、表观基因组学、基因组图谱和预测性转录建模 数据集。这些技术将被用来回答CSC生物学中几个长期悬而未决的问题。 我们将阐明CSCs是否可以通过转录重编程来自非CSCs，测试CSCs的作用 染色质结构在CSC过程中促进转录可塑性的作用，并探讨其可能性 作为一种新的治疗策略，转录重新编程CSCs以退出干细胞状态。的方方面面 技术开发将以CSC生物试验台的需求为导向，通过一系列研究 反馈循环。从长远来看，这种单细胞纳米成像技术将有助于全面 了解结构、物理化学和分子基因组事件之间的复杂相互作用。 我们预计，这些融合研究将为CSC生物学提供新的见解，而这是不可能的 通过使用任何单一方法来揭示，并为确定治疗策略打开新的机会。