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Imaging nanoscale chromatin folding in early carcinogenesis

早期致癌过程中纳米级染色质折叠的成像

基本信息

批准号：
10223251
负责人：
Yang Liu
金额：
$ 45.75万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10223251
关键词：
Adenocarcinoma Affect Archives Biological Cells ChIP-seq Characteristics Chromatin Chromatin Structure Clinical Clinical Management Colonoscopy Colorectal Colorectal Adenoma Colorectal Cancer Colorectal Neoplasms Computer software DNA Damage DNA biosynthesis Data Development Distal Early Diagnosis Evaluation Event Fluorescence Fluorescence Microscopy Formalin Gene Expression Genes Genome Image Image Analysis Indolent Intestines Lesion Location Maintenance Malignant - descriptor Malignant Neoplasms Microscopy Molecular Molecular Profiling Nanoscopy Nobel Prize Normal tissue morphology Ontology Optics Outcome Paraffin Embedding Pathology Pathway interactions Patient Care Patients Preparation Prevention strategy Preventive Protocols documentation Recurrence Reproducibility Resolution Risk Sampling Structural defect Structure System Techniques Tissue Embedding Tissue Sample adenoma base biological research cancer diagnosis cancer risk carcinogenesis high risk high throughput analysis imaging system improved innovation intestinal tumorigenesis light microscopy molecular imaging mouse model nanoscale neoplastic cell novel premalignant reconstruction research clinical testing risk stratification screening success transcriptome sequencing tumor tumor growth

项目摘要

PROJECT ABSTRACT This application is to evaluate the potential of a super-resolution microscopy system to image disrupted nanoscale chromatin folding as an early event in carcinogenesis and explore its potential to improve cancer risk stratification. Abnormal chromatin structure is among the most universal characteristics of tumor cells and has been used for clinical cancer diagnosis for two centuries. However, due to the diffraction-limited resolution of conventional light microscopy, only microscale structural abnormalities can be observed. As a result, cells undergoing early stages of malignant transformation often appear normal. Such limitation in image resolution has compromised our ability to accurately risk-stratify precursor lesions or distinguish aggressive from indolent forms. Recent advances in super-resolution fluorescence nanoscopy now enable us to image molecular-level chromatin structure down to a resolution of ~20-30 nm. Our group recently improved the throughput and robustness in stochastic optical reconstruction microscopy (STORM)-based super-resolution microscopy and enabled robust imaging of chromatin folding on the most widely used clinical samples. Built upon our preliminary studies that revealed a significant and gradual disruption of nanoscale chromatin folding in early carcinogenesis, this project will first further confirm the disrupted chromatin folding that accompanies carcinogenesis and identify their molecular characteristics and functional consequences. Second, we will optimize the workflow of super-resolution imaging system, sample preparation and image analysis to enable efficient and reproducible analysis of nanoscale chromatin folding in clinical tissue samples. We will also validate our finding of disrupted chromatin folding in patients with various colorectal precursor lesions and cancer. Third, we will evaluate the potential of imaging nanoscale chromatin folding to in patients with colorectal adenomatous polyps. This study will establish the scientific basis and underlying molecular profile of disrupted nanoscale chromatin folding in early carcinogenesis, opening a new avenue for risk stratification, facilitating the development and evaluation of new preventive strategies.

项目摘要本申请是为了评估潜在的超分辨率显微镜系统的图像中断纳米级染色质折叠作为癌发生的早期事件，并探索其改善癌症的潜力危险分层异常染色质结构是肿瘤细胞最普遍的特征之一，用于临床癌症诊断已有两个世纪。然而，由于衍射极限分辨率传统的光学显微镜，只能观察到微观结构异常。因此，细胞经历恶性转化的早期阶段通常表现正常。图像分辨率的这种限制已经损害了我们准确地对前驱病变进行风险分层或区分侵袭性和惰性的能力， forms.超分辨率荧光纳米显微镜的最新进展使我们能够在分子水平上成像染色质结构的分辨率低至约20-30 nm。我们小组最近提高了吞吐量，基于随机光学重构显微镜（STORM）的超分辨率显微镜的鲁棒性，能够在最广泛使用的临床样品上对染色质折叠进行稳健成像。建立在我们的初步研究显示，在早期，致癌作用，该项目将首先进一步证实，伴随着破坏染色质折叠致癌作用，并确定其分子特征和功能后果。二是优化超分辨率成像系统、样品制备和图像分析的工作流程，临床组织样品中纳米级染色质折叠的高效和可重复分析。我们还将证实了我们在各种结直肠前病变患者中染色质折叠破坏的发现，癌第三，我们将评估成像纳米染色质折叠的潜力，结直肠腺瘤性息肉。这项研究将建立以下的科学基础和基础分子特征在早期癌变过程中破坏了纳米级染色质折叠，为风险分层开辟了新途径，促进制定和评价新的预防战略。