Spatially-delineated System-level Analyses and Control of Cytoskeletal Regulation
细胞骨架调控的空间描绘系统级分析和控制
基本信息
- 批准号:8846120
- 负责人:
- 金额:$ 30.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-06-01 至 2016-02-29
- 项目状态:已结题
- 来源:
- 关键词:ActinsAdaptor Signaling ProteinAddressAffectArchitectureBiological AssayBundlingCancerousCell LineCell ShapeCell modelCell physiologyCellsCellular MorphologyClinicalColorComplexCytoskeletal FilamentsCytoskeletal ProteinsCytoskeletonDNADevelopmentDevelopmental ProcessDiseaseEngineeringEnvironmental Risk FactorGene ExpressionGenetic EngineeringGoalsHealthHumanImageImage AnalysisImaging TechniquesImmunofluorescence MicroscopyIndividualInvadedLifeLinkMCF10A cellsMDA MB 231Malignant NeoplasmsMapsMechanicsMediator of activation proteinMethodsMicroscopyMicrotubulesMolecularMotorNanotechnologyNeoplasm MetastasisNoiseOncogenicOpticsPathway interactionsPatternPhenotypePhysiological ProcessesPhytochromePlasticsPopulationPropertyProteinsRegulationRegulatory PathwayResearch PersonnelResolutionShapesSignal TransductionSpatial DistributionStagingStreamStructureSystemSystems BiologyTechniquesTechnologyTissuesTubulinWorkbasecancer cellcancer therapycell behaviorcell motilitygenetic regulatory proteinimprovedinsightnanoscalenew technologynoveloptical switchoutcome forecastoverexpressionprotein complexprotein distributionprotein expressionprotein functionreconstructionresponsescaffoldsingle moleculestathminsynthetic biologytherapeutic targettooltumor progression
项目摘要
DESCRIPTION (provided by applicant): Many physiological processes require cells to adaptively regulate their morphological and motile properties in response to local environmental factors and conditions. Cells gain such control by employing numerous cytoskeletal regulatory proteins (CRPs) that function collectively to generate, maintain and remodel different forms of actin and microtubule cytoskeletal structures. The overexpression of several CRPs in many forms of cancer been associated with poor prognosis. Yet, the impact of these perturbations on cytoskeletal regulation and oncogenic cell behaviors is largely unknown. While focusing on a class of CRPs believed to function as master cytoskeletal regulators (IQGAPs, WAVEs), this project will develop a new multi-scale approach to dissect composite states of CRP networks and establish functional relationships relating them to morphodynamic cell behaviors. Our approach integrates tools from the fields of synthetic biology, DNA nanotechnology, super-resolution microscopy, and systems biology in order to: (i) modulate the states of individual and multiple CRPs in cells; (ii) characterize their nanometer-scale localization patterns; and (iii) determine how CRP network states and composite morphological cell phenotypes respond mechanistically to perturbations. Expression-based perturbations will be introduced using novel gene expression technologies that provide precise and uniform control over mammalian protein expression in a cell population while introducing minimal disruptions to cell physiology. Such control will open new opportunities to screen phenotypic responses to specific CRP perturbations in high-throughput imaging assays while we adjust the expression levels and spatial distributions of single and multiple CRPs (Aim 1). Spatially-delineated, network- level analyses of CRP distributions will be enabled by a new, single-molecule 'barcoding' super resolution imaging procedure that offers opportunities to characterize the localization patterns of
several dozens of CRPs (and potentially many more) simultaneously within the same cell, while also allowing ultra-structural features of actin and microtubule networks to be resolved (Aim 2). These new technologies will be linked through computational image analyses and state machine modeling of cell responses in order to identify distinct cell phenotypes and predict their responses to CRP perturbations (Aim 3). The synergistic collaborative effort of three investigators with complementary expertise will improve the understanding of CRP network function, thereby promoting the development of new disease treatments.
描述(由申请人提供):许多生理过程需要细胞适应性地调节其形态和运动特性,以响应局部环境因素和条件。细胞通过使用许多细胞骨架调节蛋白(CRP)来获得这种控制,这些蛋白共同发挥作用以产生、维持和重塑不同形式的肌动蛋白和微管细胞骨架结构。在许多形式的癌症中,几种CRP的过表达与不良预后相关。然而,这些扰动对细胞骨架调节和致癌细胞行为的影响在很大程度上是未知的。在关注一类被认为起主要细胞骨架调节剂(IQGAP,WAVE)作用的CRP的同时,该项目将开发一种新的多尺度方法来解剖CRP网络的复合状态,并建立与形态动力学细胞行为相关的功能关系。我们的方法整合了合成生物学,DNA纳米技术,超分辨率显微镜和系统生物学领域的工具,以便:(i)调节细胞中单个和多个CRP的状态;(ii)表征其纳米尺度的定位模式;(iii)确定CRP网络状态和复合形态细胞表型如何机械地响应扰动。将使用新的基因表达技术引入基于表达的扰动,该技术提供对细胞群体中哺乳动物蛋白质表达的精确和均匀控制,同时对细胞生理学引入最小的干扰。这样的控制将打开新的机会,筛选表型反应的特定CRP扰动在高通量成像检测,而我们调整的表达水平和空间分布的单一和多种CRP(目标1)。一种新的单分子“条形码”超分辨率成像程序将能够对CRP分布进行空间划定的网络级分析,该程序提供了表征CRP定位模式的机会。
同时在同一细胞内检测几十种CRP(可能更多),同时还可以解析肌动蛋白和微管网络的超微结构特征(目的2)。这些新技术将通过计算图像分析和细胞反应的状态机建模相关联,以识别不同的细胞表型并预测它们对CRP扰动的反应(目标3)。三位具有互补专业知识的研究者的协同合作努力将提高对CRP网络功能的理解,从而促进新疾病治疗方法的开发。
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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Gabor Balazsi其他文献
Gabor Balazsi的其他文献
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{{ truncateString('Gabor Balazsi', 18)}}的其他基金
Dynamics and evolution of synthetic and natural gene regulatory networks
合成和天然基因调控网络的动力学和进化
- 批准号:
10707390 - 财政年份:2017
- 资助金额:
$ 30.37万 - 项目类别:
Dynamics and evolution of synthetic and natural gene regulatory networks
合成和天然基因调控网络的动力学和进化
- 批准号:
9459959 - 财政年份:2017
- 资助金额:
$ 30.37万 - 项目类别:
Dynamics and evolution of synthetic and natural gene regulatory networks
合成和天然基因调控网络的动力学和进化
- 批准号:
9897606 - 财政年份:2017
- 资助金额:
$ 30.37万 - 项目类别:
Administrative Supplement: Dynamics and evolution of synthetic and natural gene regulatory networks
行政补充:合成和天然基因调控网络的动态和进化
- 批准号:
10388886 - 财政年份:2017
- 资助金额:
$ 30.37万 - 项目类别:
Integration of Diverse Inputs Determines Developmental Outcomes
不同输入的整合决定发展结果
- 批准号:
9291964 - 财政年份:2016
- 资助金额:
$ 30.37万 - 项目类别:
Integration of Diverse Inputs Determines Developmental Outcomes
不同输入的整合决定发展结果
- 批准号:
8887426 - 财政年份:2015
- 资助金额:
$ 30.37万 - 项目类别:
Integration of Diverse Inputs Determines Developmental Outcomes
不同输入的整合决定发展结果
- 批准号:
9243266 - 财政年份:2015
- 资助金额:
$ 30.37万 - 项目类别:
Spatially-delineated System-level Analyses and Control of Cytoskeletal Regulation
细胞骨架调控的空间描绘系统级分析和控制
- 批准号:
8489915 - 财政年份:2013
- 资助金额:
$ 30.37万 - 项目类别:
Spatially-delineated System-level Analyses and Control of Cytoskeletal Regulation
细胞骨架调控的空间描绘系统级分析和控制
- 批准号:
9012833 - 财政年份:2013
- 资助金额:
$ 30.37万 - 项目类别:
Mapping and modeling host-pathogen interactions in TB latency and reactivation
结核病潜伏期和再激活过程中宿主-病原体相互作用的绘制和建模
- 批准号:
8052426 - 财政年份:2010
- 资助金额:
$ 30.37万 - 项目类别: