Research Test-Bed Unit

研究试验台装置

• 批准号: 10539329
• 负责人: Daniela E Matei
• 金额: $ 55.91万
• 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/10539329
• 关键词: 3-Dimensional; ATAC-seq; Address; Automobile Driving; Back; Beds; Biological; Cancer Model; Cell Differentiation process; Cells; ChIP-seq; Chemoresistance; Chromatin; Chromatin Structure; Complex; Computer Analysis; Computer Models; Coupled; Coupling; Data; Disease; Environment; Epigenetic Process; Event; Feedback; Frequencies; Gene Expression; Genetic Transcription; Genome Mappings; Genomics; Goals; Hi-C; Image; Imaging Device; Imaging Techniques; Imaging technology; Knowledge; Malignant Neoplasms; Malignant neoplasm of ovary; Maps; Modality; Modeling; Modification; Molecular; Molecular Analysis; Molecular Computations; Molecular Conformation; Outcome; Pathway interactions; Pattern; Phenotype; Platinum; Pluripotent Stem Cells; Population; Property; Recurrence; Relapse; Repression; Research; Resistance; Resolution; Resources; Science; Source; Technology; Testing; Theoretical model; Tissues; Universities; Work; cancer cell; cancer stem cell; chemotherapy; conventional therapy; epigenome; epigenomics; frontier; genome-wide; genomic profiles; high resolution imaging; histone modification; imaging modality; imaging platform; in vivo; inhibitor; innovation; nanoimaging; nanomaterials; nanoscale; physical property; pressure; programs; refractory cancer; self-renewal; single cell mRNA sequencing; stem cell therapy; stem cells; stemness; stressor; superresolution imaging; targeted agent; technology development; technology research and development; transcription factor; transcriptional reprogramming; transcriptome; transcriptomics; tumor; tumor initiation; tumor microenvironment; tumor progression; tumorigenic

Research Test-Bed Unit: PROJECT SUMMARY The overall goal of the U54 Northwestern University Center for Chromatin Nanoimaging in Cancer (NU-CCNIC) is to develop and deploy a multi-scale chromatin nanoimaging platform together with molecular analyses and computational modeling to characterize chromatin structure and transcriptional patterns associated with the cancer stem cell (CSC) and chemoresistance phenotype. The immediate application of the proposed studies will be ovarian cancer, a malignancy of unmet need. It has been speculated that CSCs represent the reservoir from which recurrent, chemotherapy-resistant tumors arise. The key biological question addressed by this Center is whether reprogramming of the transcriptome through epigenetic and chromatin organization-regulated mechanisms leads to significant transcriptional plasticity, which is critical for CSCs to withstand and survive stressors in the tumor environment, driving tumor initiation and progression. As part of NU-CCNIC, the Research Test-Bed Unit (RTB) will provide source materials for the nanoimaging technologies developed by the Technology Development Unit (TECH). These resources include cells and tissues at various transition points between stem cell and non-stem cell phenotypes and between chemotherapy-sensitive and resistant states. The studies conducted by the RTB will test the applicability of the Nanoscale Chromatin Imaging and Analysis (nano- ChIA) platform and provide feedback to optimize its use. In addition, the RTB will perform state-of-the-art computational genomic analyses of CSCs and chemotherapy-resistant cells, including single-cell mRNA sequencing and genome mapping (e.g., Hi-C, ATAC-sequencing and ChIP-sequencing). The specific objectives of this unit are: 1) To identify CSC-specific epigenomic features and 3D chromatin packing conformations by integrating genome-wide maps of chromatin accessibility, contact frequency and gene expression networks with high resolution nano-scale chromatin imaging features. 2) To identify whether the transition to a chemotherapy-resistant state promotes stemness-like chromatin packing and conformation. Locus specific epigenetic manipulations will be coupled with high resolution imaging technologies to investigate resistant-state specific 3D chromatin packing and its relation to the CSC state. 3) To discover how global epigenome manipulations induced by small enzymatic inhibitors block stemness and chemo-resistance through alterations of chromatin packing. In all, the integrated interrogation of cancer through chromatin nanoimaging methods (TECH) and genome-wide mapping (RTB) will discover how transcriptional plasticity of CSCs and chemo-resistant cancer cells is regulated. The project is at the forefront of the field by using highly innovative molecular and nanometer-scale chromatin imaging technologies to better understand the relationship between higher level chromatin structure and key drivers of stemness and chemo-resistance in a disease that remains lethal and difficult to treat.

研究试验台单位：项目摘要 U 54西北大学癌症染色质纳米成像中心（NU-CCNIC）的总体目标 是开发和部署多尺度染色质纳米成像平台以及分子分析， 计算建模，以表征染色质结构和转录模式相关的 癌症干细胞（CSC）和化学抗性表型。拟议研究的立即实施将 是卵巢癌，一种需求未得到满足的恶性肿瘤。据推测，CSC代表了来自 复发的耐化疗的肿瘤。该中心解决的关键生物学问题是 是否通过表观遗传和染色质组织调节转录组的重编程 这种机制导致了显著的转录可塑性，这对于CSC的耐受和存活至关重要。 肿瘤环境中的应激源，驱动肿瘤的发生和发展。作为NU-CCNIC的一部分， 测试台单元（RTB）将为纳米成像技术提供源材料， 技术开发股。这些资源包括各个转变点的细胞和组织 干细胞和非干细胞表型之间以及化疗敏感和耐药状态之间的差异。的 RTB进行的研究将测试纳米染色质成像和分析（纳米- ChIA）平台，并提供反馈以优化其使用。此外，RTB将执行最先进的 CSC和化疗耐药细胞的计算基因组分析，包括单细胞mRNA 测序和基因组作图（例如，Hi-C、ATAC测序和ChIP测序）。具体 本单元的目标是：1）鉴定CSC特异性表观基因组特征和3D染色质包装 通过整合染色质可及性、接触频率和基因的全基因组图谱， 表达网络与高分辨率纳米级染色质成像功能。2)以识别 向化疗抗性状态的转变促进了干细胞样染色质的堆积和构象。基因座 特定的表观遗传操作将与高分辨率成像技术相结合， 抗性状态特异性3D染色质包装及其与CSC状态的关系。3)为了发现全球 由小酶抑制剂诱导的表观基因组操纵通过以下途径阻断干性和化学抗性： 染色质包装的改变。总而言之，通过染色质纳米成像对癌症的综合审讯 方法（TECH）和全基因组作图（RTB）将发现CSC的转录可塑性， 化疗耐药癌细胞是受调节的。该项目是在该领域的前沿，通过使用高度创新的 分子和纳米级染色质成像技术，以更好地了解 更高水平的染色质结构和疾病中的干性和耐药性的关键驱动因素， 致命且难以治疗