Super-resolution microscopy for dynamic analysis of focal enhancer amplifications in cancer

用于癌症焦点增强子扩增动态分析的超分辨率显微镜

基本信息

批准号：
10170545
负责人：
Anders Sejr Hansen
金额：
$ 38万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
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：
2021-04-05 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10170545
关键词：
3-Dimensional A549 Acute Address Adenocarcinoma Cell Affect Automobile Driving Body of uterus Cancer Etiology Carcinoma Cells Chemicals Code Communication Communities DNA Disputes Distal Elements Endometrial Carcinoma Enhancers Event Gene Activation Gene Expression Genes Genetic Diseases Genetic Enhancer Element Genetic Transcription Genome Genomics Goals Histones Human Image Individual Label Lung Adenocarcinoma MYC gene Malignant Epithelial Cell Malignant Neoplasms Maps Measures Mediating Methods Microscopy Modeling Molecular Mutation Oncogenes Patients Population Proteins Regulation Resolution Running Structure System Techniques Technology Testing Time TimeLine Tumorigenicity Untranslated RNA Visualization base blind cancer genetics cell type cellular imaging experimental study genome editing imaging approach imaging modality imaging platform imaging study innovation live cell imaging nanometer overexpression promoter spatiotemporal targeted treatment technological innovation

项目摘要

Project Summary Cancer is often thought of as a genetic disease. For example, specific protein-coding mutations can activate cancer-causing oncogenes. However, cancer-causing oncogene can also be activated by alterations to non-coding DNA. Specifically, enhancers are non-coding DNA elements that can activate gene expression across vast genomic distances. In numerous cancers, genetic alterations cause enhancers to over-activate cancer-causing oncogenes. This is also referred to as enhancer hijacking. Here we focus on epithelial cancers, where enhancers that activate the MYC oncogene get duplicated and focally amplified. This correlates with higher MYC expression and increased tumorigenicity. But the molecular mechanisms are not well understood. Achieving a mechanistic understanding is important since it may identify molecular ‘Achilles Heels’ that can be targeted therapeutically. Achieving an understanding of the mechanism of enhancer action in general and enhancer hijacking in cancer in general requires an ability to measure at high spatiotemporal precision enhancer-gene communication in living cells. The proposed project will establish and validate such a platform based on super-resolution microscopy, which make it possible to track individual enhancers and genes with a precision of ten nanometers in living cells as well as gene activity in real time. Significant efforts will be devoted to validating the super- resolution microscopy approach through extensive control experiments. Significant efforts will also be devoted to disseminating the technological innovations and know-how to the greater community. In summary, we propose to establish and validate an innovative and integrative experimental and computational super-resolution microscopy platform for studying focal enhancer amplifications. While our initial focus is on amplifications of MYC enhancers in epithelial cancers, the proposed platform is likely to find widespread use beyond MYC.

项目摘要癌症通常被认为是一种遗传疾病。例如，特定的蛋白质编码突变可以激活引起癌症的致癌基因。但是，通过改变非编码DNA。具体而言，增强子是可以激活基因表达的非编码DNA元素跨越巨大的基因组距离。在众多癌症中，遗传改变会导致增强子过度活化引起癌症的致癌基因。这也称为增强剂劫持。在这里，我们专注于上皮癌，在这种癌症中激活Myc癌基的增强剂会重复并局部放大。这与较高的MYC表达和增加的肿瘤性相关。但是分子机制尚不清楚。实现机械理解很重要，因为它可能识别可以通过治疗方法靶向的分子“阿喀琉斯高跟鞋”。一般而言，了解增强器动作的机制，并在一般而言，癌症需要在高空间时间精度增强子 - 基因交流下测量的能力在活细胞中。拟议的项目将根据超分辨率建立并验证该平台显微镜，这使得可以以十纳米精度跟踪单个增强子和基因在活细胞和基因活性中实时。重大努力将致力于验证超级通过广泛的控制实验的分辨显微镜方法。重大努力也将被奉献传播技术创新，并向更大的社区进行专业知识。总而言之，我们建议建立和验证一个创新且综合的实验性和用于研究焦点增强子扩增的计算超分辨率显微镜平台。而我们的最初重点是上皮癌中MYC增强剂的扩增，建议的平台可能会发现超越MYC的宽度使用。