Research Test-Bed Unit

研究试验台装置

基本信息

批准号：
10375271
负责人：
Daniela E Matei
金额：
$ 57.72万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
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/10375271
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 Methods Modality Modeling Modification Molecular Molecular Analysis Molecular Computations Molecular Conformation Outcome Pathway interactions Pattern Phenotype Platinum Pluripotent Stem Cells Population Problem Solving Property Recurrence Relapse Research Resistance Resolution Resources Science Source Technology Testing Theoretical model Tissues Universities Work XCL1 gene anticancer research base cancer cell cancer stem cell chemotherapy conventional therapy epigenome epigenomics frontier genome-wide genomic profiles high resolution imaging histone modification in vivo inhibitor innovation molecular scale nano nanoimaging nanoscale physical property pressure programs refractory cancer self-renewal single cell mRNA sequencing stem cells stemness stressor targeted agent technology development technology research and development transcription factor transcriptional reprogramming transcriptome transcriptomics tumor tumor initiation tumor microenvironment tumor progression tumorigenic

项目摘要

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.

研究试验台单元：项目摘要 U54西北大学癌症染色质纳米成像中心（NU-CCNIC）的总体目标旨在开发和部署多尺度染色质纳米成像平台以及分子分析和计算模型来表征染色质结构和与相关的转录模式癌症干细胞（CSC）和化疗耐药表型。拟议研究的立即应用将卵巢癌是一种未满足需求的恶性肿瘤。据推测，CSC 代表了来自从而出现复发性、化疗耐药的肿瘤。该中心解决的关键生物学问题是转录组的重编程是否通过表观遗传和染色质组织调节机制导致显着的转录可塑性，这对于 CSC 的承受和生存至关重要肿瘤环境中的压力源，驱动肿瘤的发生和进展。作为 NU-CCNIC 的一部分，该研究试验台单元（RTB）将为该研究所开发的纳米成像技术提供源材料技术开发单位（TECH）。这些资源包括处于不同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。这 RTB 进行的研究将测试纳米级染色质成像和分析（纳米级染色质成像和分析）的适用性 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）。具体的本单元的目标是： 1) 识别 CSC 特异性表观基因组特征和 3D 染色质堆积通过整合染色质可及性、接触频率和基因的全基因组图谱来确定构象具有高分辨率纳米级染色质成像特征的表达网络。 2) 判断是否向化疗耐药状态的转变会促进干性样染色质堆积和构象。轨迹特定的表观遗传操作将与高分辨率成像技术结合起来进行研究抗性状态特异性 3D 染色质堆积及其与 CSC 状态的关系。 3) 发现全球性小酶抑制剂诱导的表观基因组操作可通过抑制干性和化疗耐药性染色质包装的改变。总之，通过染色质纳米成像对癌症进行综合研究方法 (TECH) 和全基因组作图 (RTB) 将发现 CSC 的转录可塑性和化疗耐药的癌细胞受到调节。该项目采用高度创新的技术，处于该领域的前沿分子和纳米级染色质成像技术，以更好地了解两者之间的关系更高水平的染色质结构以及疾病干性和化疗耐药性的关键驱动因素致命且难以治疗。