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.

总体而言：项目摘要 癌症干细胞（CSC）在促进肿瘤对治疗的抵抗力和治疗后复发方面发挥着关键作用。 这对成功的抗癌疗法的发展构成了关键障碍。 转录重编程和可塑性在 CSC 状态内外发挥着关键作用，而这反过来又是 相互依赖于染色质三维​​ (3D) 结构的调节功能、表观遗传状态、 和其他分子事件的需求阻碍了我们对基本 CSC 生物学的理解。 用于细胞纳米级成像技术，提供有关 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重分子成像 我们建议建立西北大学染色质中心。 癌症纳米成像 (NU-CCNIC) 旨在解决细胞纳米级成像的这一基本技术差距 并部署新技术来解决 CSC 生物学的基础知识差距。 汇聚了细胞纳米级成像、计算成像、分子建模、计算 该中心将开发、测试、验证、迭代和部署一个集成的基因组学、CSC 生物学和肿瘤学。 并共同注册了多尺度染色质纳米成像平台，该平台将包括三个“嵌套娃娃”成像 技术：染色质扫描透射电子显微镜、光学光谱超分辨率 纳米成像平台将实现定量成像。 从根本上讲，染色质结构和高度多重分子和基因特异性定位 长度尺度接近 1 nm 分辨率，包括统计显着细胞群的成像和 纳米成像平台将在长时间的随访时间内具有高时间分辨率的活细胞。 连接计算基因组学、表观基因组学、基因组作图和预测转录模型 这些技术将用于回答 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源自非CSCs，测试其作用 染色质结构在促进 CSC 过程中转录可塑性方面的作用，并探索 转录重编程 CSC 以退出干状态作为一种新的治疗策略。 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 从长远来看，这种单细胞纳米成像技术将有助于全面发展。 了解结构、物理化学和分子基因组事件之间复杂的相互作用。 我们预计这些融合研究将为 CSC 生物学提供新的见解，这是不可能的 使用任何单一方法进行揭示，并为确定治疗策略提供新的机会。