Multiplexed Measurements of Protein Dynamics and Interactions at Extreme Resoluti
极端分辨率下蛋白质动力学和相互作用的多重测量
基本信息
- 批准号:7852460
- 负责人:
- 金额:$ 214万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-09-30 至 2014-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAlgorithmsArtsBiologyCellsComplexConfocal MicroscopyDetectionDiseaseEnergy TransferGoalsImageImage AnalysisImaging technologyLifeMeasurementMeasuresMethodsMicroscopeMicroscopyOpticsPathway interactionsProtein DynamicsProteinsPublic HealthResolutionScanningSignal PathwaySignal TransductionSignaling ProteinTechnologyTherapeuticTimeWorkabstractingfluorophorenew technologynovelprotein complexpublic health relevanceresponsesuccess
项目摘要
DESCRIPTION (Provided by the applicant)
Abstract: My goal is to develop state-of-art imaging technology that can measure protein complex formation and protein networks in a multiplexed fashion with spatial resolution beyond that of the optical microscopy. At present, a major limitation to clarifying the dynamics of a particular signaling cascade is the inability to visualize multiple (>4) proteins and their interactions simultaneously in real time in the living cell. This is due in part to the interference of spectrally similar species (including cellular autofluorescence) and the mismatch between the spatial resolution of the confocal microscope and the scale of protein interactions. Computational and experimental approaches can help to elucidate many of these interactions, but not all. Specialized microscopy methods have been developed to address some aspects of the problem, but to date, no technology has demonstrated true multiplexed (simultaneous, not sequential) detection of >4 proteins and their complex formation in living cells at spatial resolutions >100 nm. This type of detection is critical for unraveling protein interaction network details, and my proposed work will address that. Specifically, I will: 1) implement novel emission-scanning hyperspectral confocal microscopy hardware to collect information from large numbers of fluorescent species simultaneously at spatial resolution beyond that of the optical microscope. 2) develop corresponding algorithms to spectrally unmix the 6D (X, Y, Z, excitation ?, emission ?, and time) images and provide accurate measurements of fluorophore concentrations even in the presence of energy transfer. This creative approach alleviates limitations of existing multicolor technology by extending my expertise in livecell hyperspectral imaging technology into the "super-resolution" realm. Its success will be enabled by robust multivariate image analysis algorithms. This advance will have far-reaching impact in exploring signaling pathways and networks in biology and biomedicine.
Public Health Relevance: The complex symphony of signaling networks still remains a mystery. This project will develop a novel technology to unravel the details of signaling protein networks and pathways with extreme accuracy and spatial resolution. This work is very relevant to Public Health because cell signaling cascades control and regulate response to disease or therapeutic countermeasures.
描述(由申请人提供)
摘要:我的目标是开发最先进的成像技术,以超过光学显微镜的空间分辨率,以多路复用的方式测量蛋白质复合体的形成和蛋白质网络。目前,阐明特定信号级联的动力学的一个主要限制是无法在活细胞中实时地同时可视化多个(>;4)蛋白质及其相互作用。这在一定程度上是由于光谱相似的物种(包括细胞自发荧光)的干扰,以及共焦显微镜的空间分辨率和蛋白质相互作用的规模之间的不匹配。计算和实验方法可以帮助阐明这些相互作用中的许多,但不是全部。已经开发了专门的显微镜方法来解决这个问题的某些方面,但到目前为止,还没有技术证明真正的多路(同时,而不是顺序)检测>;4蛋白质及其在活细胞中以空间分辨率>;100 nm形成的复合体。这种类型的检测对于解开蛋白质相互作用网络的细节至关重要,我提议的工作将解决这一问题。具体地说,我将:1)实现新颖的发射扫描高光谱共焦显微镜硬件,以超出光学显微镜的空间分辨率同时收集大量荧光物种的信息。2)开发相应的算法来对6D(X、Y、Z、激发?、发射?和时间)图像进行光谱分解,并提供即使在存在能量转移的情况下也能准确测量荧光团浓度的算法。这种创造性的方法通过将我在LiveCell高光谱成像技术方面的专业知识扩展到“超分辨率”领域,缓解了现有多色技术的局限性。它的成功将得益于稳健的多变量图像分析算法。这一进展将对探索生物和生物医学中的信号通路和网络产生深远影响。
与公共健康相关:信令网络的复杂交响乐仍然是一个谜。该项目将开发一种新技术,以极高的精度和空间分辨率解开信号蛋白质网络和通路的细节。这项工作与公共卫生非常相关,因为细胞信号级联控制和调节对疾病或治疗对策的反应。
项目成果
期刊论文数量(0)
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专利数量(2)
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