Super-Resolution Imaging of Higher-Order Heterochromatin Structure for Early Detection of Lung Carcinogenesis

高阶异染色质结构的超分辨率成像用于早期检测肺癌

• 批准号: 10592368
• 负责人: Laura P. Stabile
• 金额: $ 18.21万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10592368
• 关键词: Age; Biological Markers; Cancer Etiology; Cancer Patient; Carcinogens; Cells; Cessation of life; Characteristics; Chromatin; Chromatin Structure; Chronic Obstructive Pulmonary Disease; Cigarette Smoker; Clinical; Data; Data Collection; Detection; Development; Diagnosis; Early Diagnosis; Epigenetic Process; Epithelial Cells; Event; Exhibits; Eye; Formalin; Goals; Heterochromatin; Human; Image; Image Analysis; Invasive Lesion; Light Microscope; Lung; Lung Adenocarcinoma; Lung Neoplasms; Machine Learning; Malignant Neoplasms; Malignant neoplasm of lung; Microscopy; Molecular; Molecular Structure; Morbidity - disease rate; Mus; Normal Cell; Normal tissue morphology; Optics; Paraffin Embedding; Pathologist; Pathway interactions; Patients; Preparation; Prevention; Prognosis; Protocols documentation; Recommendation; Research; Resolution; Risk; Risk Assessment; Risk Factors; Sampling; Screening for cancer; Sensitivity and Specificity; Smoker; Smoking; Specimen; Sputum; Structure; Structure of parenchyma of lung; System; Techniques; Time; Tissues; Tobacco-Associated Carcinogen; Training; United States; Visualization; bronchial epithelium; cancer cell; carcinogenesis; cigarette smoking; clinical imaging; clinically significant; cohort; community based research; cost effective; detection method; former smoker; high resolution imaging; high risk; imaging system; improved; innovation; innovative technologies; light microscopy; low dose computed tomography; lung cancer screening; lung carcinogenesis; lung development; molecular scale; mortality; mouse model; nanometer resolution; nanoscale; neoplastic; non-smoker; novel strategies; programs; repository; sample collection; screening; single molecule; success; superresolution imaging; superresolution microscopy; tumor; tumor progression

PROJECT SUMMARY/ABSTRACT Lung cancer is the leading cause of cancer-related death in the United States. Overall, patients diagnosed with early-stage lung cancer have a much better prognosis. Cigarette smoking is the major cause of lung cancer and screening for lung cancer is currently recommended for high-risk current and former smokers. Compared with nonsmokers, smokers have an almost 30-fold increased risk of developing lung cancer. Unfortunately, despite significant efforts, early detection of lung cancer remains sub-optimal with conventional approaches suffering from high false-positive rates or limited sensitivity. Improved understanding of the early events underlying smoking-related lung cancer development is crucial to the identification of new biomarkers and targets for early detection and prevention. Further, new methods that detect those early events in lung cancer development in a non-invasive and cost-effective manner with high sensitivity and specificity are urgently needed. Recent advances in super-resolution microscopy revolutionize the field of optical microscopy and offer a new ability to visualize molecular structure at nanometer resolution that is invisible under a conventional light microscope. We propose an innovative approach to adapt super-resolution microscopy to improve the early detection of lung cancer. Our approach is built upon our recent discovery that chromatin folding becomes gradually fragmented in early lung carcinogenesis, even when cells still appear normal under conventional light microscope. Our ultimate goal is to detect such nanoscale chromatin “misfolding” in bronchial cells present in sputum to improve early detection of lung cancer. In this project, we will first establish disrupted nanoscale chromatin folding as an early event in lung carcinogenesis utilizing a mouse model of carcinogen-induced lung adenocarcinoma as well as existing well-annotated human lung tissue specimens (Aim 1). In addition, we will evaluate the feasibility of super-resolution imaging of nanoscale chromatin “misfolding” for early detection of lung cancer using existing sputum samples and data from the Pittsburgh Lung Screening Study, a community- based research cohort of current and ex-smokers, screened with low-dose computed tomography and followed for lung cancer (Aim 2).

项目概要/摘要 总体而言，肺癌是美国癌症相关死亡的主要原因。 早期肺癌的预后要好得多，吸烟是肺癌的主要原因。 目前建议对当前和既往吸烟者进行肺癌筛查。 不幸的是，与不吸烟者相比，吸烟者患肺癌的风险增加了近 30 倍。 尽管传统方法对肺癌的早期检测仍然不够理想，但仍付出了巨大的努力 患有高假阳性率或有限的敏感性对早期事件的了解。 与吸烟相关的肺癌的潜在发展对于识别新的生物标志物和 此外，还有检测肺癌早期事件的新方法。 迫切需要以非侵入性和具有成本效益的方式进行高敏感性和特异性的开发 超分辨率显微镜的最新进展彻底改变了光学显微镜领域并提供了新的解决方案。 一种以纳米分辨率可视化分子结构的新能力，这种结构在传统光下是不可见的 我们提出了一种采用超分辨率显微镜的创新方法，以改善早期的结果。 我们的方法是基于我们最近发现染色质折叠变得。 在早期肺癌发生过程中逐渐破碎，即使细胞在常规光下仍表现正常 我们的最终目标是检测支气管细胞中的这种纳米级染色质“错误折叠”。 在这个项目中，我们将首先建立扰乱的纳米级痰液以改善肺癌的早期检测。 利用致癌物诱导的肺癌小鼠模型研究染色质折叠作为肺癌发生的早期事件 腺癌以及现有注释良好的人类肺组织标本（目标 1）。 评估纳米级染色质“错误折叠”超分辨率成像用于早期检测的可行性 使用现有的痰样本和来自匹兹堡肺部筛查研究（一个社区）的数据来诊断肺癌 基于当前吸烟者和戒烟者的研究队列，通过低剂量计算机断层扫描进行筛查并进行跟踪 肺癌（目标 2）。