Mapping the Cellular Responses to DNA Double-Strand Breaks Using On-Demand CRISPR technologies and High-resolution Fluorescence Microscopy
使用按需 CRISPR 技术和高分辨率荧光显微镜绘制细胞对 DNA 双链断裂的反应
基本信息
- 批准号:10715720
- 负责人:
- 金额:$ 38.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-01 至 2028-05-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAddressAgingBindingBiochemicalCRISPR/Cas technologyCellsCellular StressChromatinChromosomal translocationComplementComplexDNADNA DamageDNA Double Strand BreakDNA RepairDNA Repair GeneDefectDevelopmentDiseaseDouble Strand Break RepairFluorescence MicroscopyGene MutationGenetic ResearchGenetic TranscriptionGenomeHumanHuman GenomeImmune systemInnate Immune SystemKineticsKnowledgeLinkMaintenanceMalignant NeoplasmsMammalian CellMapsMediatingMutationNuclearPathway interactionsProteinsResearchResearch ProposalsResolutionRoleSignal TransductionStructureTestingTubeVisualizationbiophysical techniquesenvironmental stressorgenetic approachgenome integritygenomic locusgenotoxicityhuman diseaseinsightnovelprogramsrapid detectionrepairedresponsespatiotemporaltemporal measurement
项目摘要
The integrity of the human genome is constantly challenged by
environmental and cellular stresses, resulting in various DNA damage and gene
mutations. Many proteins have evolved to rapidly detect, signal, and repair DNA
damage inside living cells, forming an orchestrated network known as DNA
damage response (DDR). Unsurprisingly, DDR defects, such as DNA repair protein
mutations, are often linked to human diseases, including developmental
abnormalities, accelerated aging, and common cancers. The past decades of
biochemical and genetic research have generated a wealth of knowledge
regarding the identities of DDR factors, their roles in genome maintenance, and
how they contribute to the diseases when they go awry. However, the detailed
spatiotemporal parameters by which DDR factors mediate DNA repair remain
largely elusive. What timescales do DDR factors search for and bind to damaged
DNA in living cells? Do DDR factors form specific structures to facilitate an
accurate repair? How does DNA damage regulate other nuclear DNA activities,
such as transcription? This research program aims to address these fundamental
questions by investigating DDR dynamics during DNA double-strand break (DSB)
repair. DSB is one of the most genotoxic DNA damage types frequently occurring
in our bodies. Recently, we have established an experimental platform that allows
quantitative visualization of DDR factors and on-demand DSB induction at specific
genomic loci and with a second-scale temporal resolution, a capability achieved
by marrying high-resolution fluorescence microscopy with the very fast
(vf)CRISPR technique pioneered by our lab. Here, we will take full advantage of
this novel platform and comprehensively map the DSB-induced dynamics of DDR
factors, chromosome translocation, and activities of transcription and cGAS in
single human cells. This study will strongly complement DSB repair research
conventionally performed in test tubes and at the ensemble level, providing
valuable mechanistic insights into DSB repair with unprecedented resolutions.
人类基因组的完整性不断受到挑战,
环境和细胞压力,导致各种DNA损伤和基因
突变。许多蛋白质已经进化到可以快速检测、发送信号和修复DNA
活细胞内的损伤,形成一个被称为DNA的精心策划的网络
损伤响应(DDR)。不出所料,DDR缺陷,如DNA修复蛋白,
突变,往往与人类疾病,包括发育
异常,加速老化和常见癌症。过去几十年
生物化学和遗传学研究产生了丰富的知识
关于DDR因子的身份,它们在基因组维护中的作用,以及
当它们出错时是如何导致疾病的。然而,详细
DDR因子介导DNA修复时空参数仍然存在
很难捉摸DDR因素搜索并绑定到损坏的时间尺度是什么
活细胞中的DNA?解除武装、复员和重返社会因素是否形成了促进
准确修复?DNA损伤如何调节其他核DNA活动,
例如转录?该研究计划旨在解决这些基本问题。
通过研究DNA双链断裂(DSB)过程中的DDR动力学问题
修复. DSB是最常见的遗传毒性DNA损伤类型之一
在我们的身体里。最近,我们建立了一个实验平台,
DDR因子的定量可视化和特定条件下的按需DSB诱导
基因组位点,并与第二规模的时间分辨率,一种能力,实现
通过将高分辨率荧光显微镜与超快的
(vf)我们实验室开创的CRISPR技术。在这里,我们将充分利用
这一新的平台,并全面映射DSB诱导的DDR动力学
因子,染色体易位,以及转录和cGAS的活性,
单个人体细胞这项研究将有力地补充DSB修复研究
传统上在试管中进行,并在合奏水平,提供
以前所未有的分辨率对DSB修复进行有价值的机械见解。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Yang Liu其他文献
Formal Verification of Process Layer with Petri nets and Z
使用 Petri 网和 Z 对过程层进行形式化验证
- DOI:
10.4156/aiss.vol5.issue1.9 - 发表时间:
2013-01 - 期刊:
- 影响因子:0
- 作者:
Yang Liu;Jinzhao Wu;Rong Zhao;Hao Yang;Zhiwei Zhang - 通讯作者:
Zhiwei Zhang
An efficient p-ECR move based on maximum likelihood by neighbor joining
基于邻居加入最大似然的高效 p-ECR 移动
- DOI:
- 发表时间:
- 期刊:
- 影响因子:3
- 作者:
Yang Liu;Jian-Fu Li;Mao-Zu Guo, - 通讯作者:
Mao-Zu Guo,
Secure multi-label data classification in cloud by additionally homomorphic encryption
通过额外的同态加密在云中保护多标签数据分类
- DOI:
- 发表时间:
2018 - 期刊:
- 影响因子:0
- 作者:
Yi Liu Yu Luo;Youwen Zhu;Yang Liu;Xingxin Li - 通讯作者:
Xingxin Li
Requirement Verification of Networked Software Goals with Multi-valued Logic
具有多值逻辑的网络化软件目标的需求验证
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
Yang Liu;Jinzhao Wu;Rong Zhao;Zhiwei Zhang;Hao Yang - 通讯作者:
Hao Yang
Yang Liu的其他文献
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{{ truncateString('Yang Liu', 18)}}的其他基金
Spatially resolved multiomics profiling of microbes and their host tissue
微生物及其宿主组织的空间分辨多组学分析
- 批准号:
10713736 - 财政年份:2023
- 资助金额:
$ 38.5万 - 项目类别:
Climate & Health Actionable Research and Translation Center
气候
- 批准号:
10835460 - 财政年份:2023
- 资助金额:
$ 38.5万 - 项目类别:
Climate & Health Actionable Research and Translation Center
气候
- 批准号:
10835461 - 财政年份:2023
- 资助金额:
$ 38.5万 - 项目类别:
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:
10435645 - 财政年份:2022
- 资助金额:
$ 38.5万 - 项目类别:
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
- 批准号:
10398183 - 财政年份:2020
- 资助金额:
$ 38.5万 - 项目类别:
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
- 批准号:
10605199 - 财政年份:2020
- 资助金额:
$ 38.5万 - 项目类别:
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
- 批准号:
10223251 - 财政年份:2020
- 资助金额:
$ 38.5万 - 项目类别:
Three dimensional nanoscale nuclear architecture mapping based taxonomy of precursor lesions for predicting colorectal cancer risk
基于三维纳米级核结构映射的前体病变分类法用于预测结直肠癌风险
- 批准号:
9756510 - 财政年份:2019
- 资助金额:
$ 38.5万 - 项目类别:
Three dimensional nanoscale nuclear architecture mapping based taxonomy of precursor lesions for predicting colorectal cancer risk
基于三维纳米级核结构映射的前体病变分类法用于预测结直肠癌风险
- 批准号:
10590702 - 财政年份:2019
- 资助金额:
$ 38.5万 - 项目类别:
Three dimensional nanoscale nuclear architecture mapping based taxonomy of precursor lesions for predicting colorectal cancer risk
基于三维纳米级核结构映射的前体病变分类法用于预测结直肠癌风险
- 批准号:
10373010 - 财政年份:2019
- 资助金额:
$ 38.5万 - 项目类别:
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