Project 3: Mechanics of Nuclei, Chromosomes and Chromatin in Cancer
项目 3:癌症中细胞核、染色体和染色质的力学
基本信息
- 批准号:8866972
- 负责人:
- 金额:$ 39.95万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-05-19 至 2020-04-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAutomobile DrivingBindingBiologicalBiological AssayCell CycleCell ExtractsCell LineCell NucleusCell physiologyCellsCellular biologyCharacteristicsChemicalsChromatinChromatin FiberChromatin LoopChromatin StructureChromosome StructuresChromosome abnormalityChromosomesClustered Regularly Interspaced Short Palindromic RepeatsComplexCrowdingDataDevelopmentDiseaseElectron MicroscopyEngineeringEpigenetic ProcessExcisionFeedbackFiberFractalsGene ExpressionGene Expression RegulationGenesGoalsHigher Order Chromatin StructureHistonesHumanImageImmunofluorescence ImmunologicInterphaseInterphase ChromosomeIonsLabelLeadLinkMagnetismMaintenanceMalignant NeoplasmsMeasurementMechanicsMetalsMetaphaseMethodologyMethodsMitosisMitotic ChromosomeModelingMolecularMolecular ModelsMutationNormal CellNuclearNuclear EnvelopeNuclear ExtractNuclear StructureOncogenicPatientsPatternPhenotypePhysicsPlayPolymersPositioning AttributePost-Translational Protein ProcessingPropertyProphaseProteinsReagentRegulatory ElementRelative (related person)ResearchResearch PersonnelResearch Project GrantsResourcesRoleSmall Interfering RNASpectrum AnalysisStatistical MechanicsStructureTechniquesTechnologyTestingTimeVariantXenograft procedurebasecancer cellcell typecohesinfluorescence imaginghistone modificationmathematical modelmolecular modelingoptical imagingprotein distributionresearch studysimulationsingle moleculestatisticstooltranscription factortumor progressiontumorigenic
项目摘要
ABSTRACT (RESEARCH PROJECT 3)
Project 3 aims to understand organization and function of chromosomes and the nucleus in cancer cells,
engaging the Center's focus on spatio-temporal dynamics of chromatin and information transfer in cancer. All
functions of the cell are ultimately controlled by the nucleus, in which genes are expressed, under elaborate
regulatory control. The molecular organization of chromosomes and the underlying chromatin is central to
gene regulation. How many copies of genes are present, what patterns of transcription factors are bound to
gene regulatory elements, which regions are heavily repressed by heterochromatinization, and which regions
carry epigenetic marks all play a central role in controlling gene expression. In cancer, these factors are often
– and usually in combination – dysregulated, with concomitant aberrant structure of the nucleus and
chromosomes. Project 3 seeks to analyze the variation in chromatin structure – from the fiber level to
chromosomes to the whole cell nucleus – using physical tools in combination with state-of-the-art cell biological
approaches. Aim 1 of the project examines the hypothesis, supported by an array of preliminary data, that the
physical organization and mechanics of chromosomes and nuclei are altered in cancer cells. This will be
tested using micromechanical studies of nuclei and chromosomes, combined fluorescence imaging of major
chromosome- and nucleus-organizing proteins, and partial-wave spectroscopy measurements of nuclear
disorder (PWS, a technology supported by the proposed Nanocytometry Core). Experiments will be carried
out in a range of tumorigenic and non-tumorigenic cell types being studied in the other Projects. Experiments
using patient-derived xenografts (PDX) will test ideas developed in cell lines in a patient disease context
(supplied by the proposed PDX Core). Aim 2 will test how removal of specific chromosome-organizing proteins
(using siRNA and CRISPR methods) affects chromosome and nuclear structure, and then will use the results
of both Aim 1 and Aim 2 in combination with Hi-C data to develop mathematical models of metaphase
chromosome and interphase nucleus organization. Aim 3 will focus on how chromatin fibers themselves are
physically altered in different cell types, in single-chromatin-fiber assembly and mechanics experiments using
nuclear extracts from cells studied in Aims 1 and 2, a primary goal being to correlate “open” or “soft” chromatin
states with specific histone modifications. The result of Project 3 will be a comprehensive study of how
chromatin and chromosomes are remodeled in cancer cells relative to normal cells, and its research will be
tightly linked to Project 1 and Project 2 via parallel studies of the same cell lines, use of the physical assays
developed in Project 3, and through cooperation on development of siRNA and CRISPR methodologies.
摘要(研究项目3)
项目3旨在了解癌细胞中染色体和细胞核的组织和功能,
参与该中心对染色质时空动力学和癌症信息传递的关注。所有
细胞的功能最终由细胞核控制,基因在细胞核中表达,
监管控制。染色体和染色质的分子组织是
基因调控基因有多少拷贝,转录因子的模式是什么
基因调控元件,哪些区域被异染色质化严重抑制,哪些区域
携带表观遗传标记的基因在控制基因表达方面都起着重要作用。在癌症中,这些因素通常
- 并且通常是组合的-失调,伴随着细胞核的异常结构,
染色体项目3旨在分析染色质结构的变化-从纤维水平到
染色体到整个细胞核-使用物理工具结合最先进的细胞生物学
接近。该项目的目标1审查了一系列初步数据支持的假设,即
在癌细胞中染色体和细胞核的物理组织和力学发生改变。这将是
使用细胞核和染色体的微机械研究进行测试,结合主要细胞的荧光成像,
染色体和细胞核组织蛋白,以及核组织蛋白的分波光谱测量
无序(PWS,由提议的纳米细胞计数核心支持的技术)。将进行实验
在其他项目中正在研究的一系列致瘤性和非致瘤性细胞类型中。实验
使用患者来源的异种移植物(PDX)将测试在患者疾病背景下的细胞系中开发的想法
(由提议的PDX核心提供)。目标2将测试如何去除特定的染色体组织蛋白
(使用siRNA和CRISPR方法)影响染色体和核结构,然后将使用结果
目的1和目的2的数学模型结合Hi-C数据建立中期的数学模型
染色体和间期核组织。目标3将集中在如何染色质纤维本身是
在不同的细胞类型中,在单染色质纤维组装和力学实验中,
目的1和2中研究的细胞核提取物,主要目标是将“开放”或“软”染色质
具有特定组蛋白修饰的状态。项目3的结果将是全面研究如何
相对于正常细胞,癌细胞中的染色质和染色体被重塑,其研究将是
通过对相同细胞系的平行研究,使用物理测定,与项目1和项目2紧密相关
在项目3中开发,并通过合作开发siRNA和CRISPR方法。
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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JOHN F MARKO其他文献
JOHN F MARKO的其他文献
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{{ truncateString('JOHN F MARKO', 18)}}的其他基金
Activities of nucleoprotein complexes visualized in single-molecule experiments
单分子实验中核蛋白复合物的活性可视化
- 批准号:
10544026 - 财政年份:2013
- 资助金额:
$ 39.95万 - 项目类别:
Activities of nucleoprotein complexes visualized in single-molecule experiments
单分子实验中核蛋白复合物的活性可视化
- 批准号:
8735170 - 财政年份:2013
- 资助金额:
$ 39.95万 - 项目类别:
Activities of nucleoprotein complexes visualized in single-molecule experiments
单分子实验中核蛋白复合物的活性可视化
- 批准号:
8856279 - 财政年份:2013
- 资助金额:
$ 39.95万 - 项目类别:
Activities of nucleoprotein complexes visualized in single-molecule experiments
单分子实验中核蛋白复合物的活性可视化
- 批准号:
8481118 - 财政年份:2013
- 资助金额:
$ 39.95万 - 项目类别:
Activities of nucleoprotein complexes visualized in single-molecule experiments
单分子实验中核蛋白复合物的活性可视化
- 批准号:
10366903 - 财政年份:2013
- 资助金额:
$ 39.95万 - 项目类别:
Activities of nucleoprotein complexes visualized in single-molecule experiments
单分子实验中核蛋白复合物的活性可视化
- 批准号:
9070466 - 财政年份:2013
- 资助金额:
$ 39.95万 - 项目类别:
DNA Information and Organization at Supranucleosomal Scales
核小体上尺度的 DNA 信息和组织
- 批准号:
7820267 - 财政年份:2009
- 资助金额:
$ 39.95万 - 项目类别:
DNA Information and Organization at Supranucleosomal Scales
核小体上尺度的 DNA 信息和组织
- 批准号:
8379859 - 财政年份:
- 资助金额:
$ 39.95万 - 项目类别:
DNA Information and Organization at Supranucleosomal Scales
核小体上尺度的 DNA 信息和组织
- 批准号:
8182399 - 财政年份:
- 资助金额:
$ 39.95万 - 项目类别:
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