Integrated visualization, control, and analysis of GEF – GTPase networks in living cells
活细胞中 GEF – GTPase 网络的集成可视化、控制和分析
基本信息
- 批准号:10612345
- 负责人:
- 金额:$ 51.49万
- 依托单位:
- 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:2021-05-01 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:ActomyosinAcuteAddressAdhesionsAdoptedAdoptionArchitectureBasic ScienceBehaviorBindingBiologicalBiomedical EngineeringBiosensorCell AdhesionCell Adhesion MoleculesCell physiologyCellsCommunitiesComplexComputing MethodologiesCoupledCytoskeletonDataDecision MakingDiseaseDyesElementsEngineeringEnvironmentEtiologyEventFamilyFeedbackFiberFluorescence Resonance Energy TransferGTP BindingGuanineGuanine Nucleotide Exchange FactorsGuanosine Triphosphate PhosphohydrolasesHomeostasisImageImage AnalysisInterdisciplinary StudyLabelMachine LearningMalignant NeoplasmsMapsMarketingMathematicsMembraneMethodsModelingModificationMolecularMolecular ConformationMorphogenesisNeighborhoodsOncogenicOrganic ChemistryOutputPathway interactionsPlayProcessProtein EngineeringProteinsProxyRegression AnalysisRegulationReportingResearchResearch Project GrantsResolutionRoleRouteSeriesSignal PathwaySignal TransductionSignal Transduction PathwaySiteSpecific qualifier valueSpecificityStatistical ModelsStimulusStructureSystemTechniquesTestingTimeTime Series AnalysisTranslatingTranslational ResearchVisualizationanalogcancer therapycell behaviorcell motilitycomputer sciencecontrol theorydata integrationdesigneconometricsguanine analoghigh dimensionalityimage processingimaging approachimaging scienceinterdisciplinary approachinterestlight emissionmathematical methodsmathematical theorymigrationmultiplexed imagingnoveloptogeneticspreservationresponserhorho GTP-Binding Proteinssingle moleculespatiotemporaltool
项目摘要
A small number of Rho family GTPases participate in a broad array of fundamental cellular behaviors.
Specificity is possible due to spatial and temporal control of GTPase “activation”; Guanine exchange factors
(GEFs) generate activated, GTP-bound GTPases with precise timing and localization, while specialized
interactions with adhesion molecules, membrane domains and other localized structures specify GEF-GTPase
interactions. GEF/GTPase circuits are complex, with localized feedbacks, multiple GEFs controlling one
GTPase, and vice versa. To dissect this spatiotemporally regulated circuitry requires imaging, and new
analytical techniques that can dissect causal relationships from imaging data. Following the intentions of PAR-
19-158 (Bioengineering Research Grants), we propose a multidisciplinary collaboration leveraging organic
chemistry, protein engineering, imaging, and computer science to fudnamentally advance signal transduction
imaging and analysis. As a biological testbed we will explore the role of GEF-GTPase interactions in cell
protrusion, single cell migration and collective migration. We will develop a generalizable approach to GEF
biosensors, and adapt our proven GTPase biosensors to image GEF and GTPase activities in the same cell.
Because GEF-GTPase interactions are heterogeneous and complex, multiplexed imaging is necessary to
quantify their relative dynamics. However, perturbation of cell behavior is especially problematic when using
two biosensors in the same cell. We will therefore develop new biosensor designs that greatly reduce cell
perturbation. Even the most precise imaging of overlapping molecular activations has not revealed causal
relationships. We will therefore adopt the framework of Granger Causality inference, which was originally
devised for financial market analysis, to extract causal connections and feedback interactions from imaging
data. Numerous steps will be necessary to translate the existing concepts of Granger causality to the analysis
of spatially and temporally distributed molecular processes. Most importantly, we will implement a schema for
Granger causality inference in multivariate time series models that will capture spatial relations, and we will
combine principles of high-dimensional statistical regression with approaches from control theory to estimate
information flows between variables that are coupled by strong feedbacks. We will also develop a novel
clustering approach that preserves the neighborhood topology of data in a high-dimensional feature space and
in the Euclidian space of the cell outline to identify signaling microdomains. Finally, to test and confirm our
hypotheses, we will use new photo-activatable and photo-inhibitable analogs of GEFs together with GTPase
biosensors to control one protein while observing another. This research plan will produce biosensors with
reduced perturbation, biosensor/optogenetic multiplexing capabilities, and image analysis/modeling
approaches necessary to shed light on the network topology of nonlinear, spatiotemporally controlled signaling
pathways. All tools will efficiently deployed to the community.
少量的Rho家族GTP酶参与了一系列基本的细胞行为。
特异性可能是由于GTP酶“激活”的空间和时间控制;鸟嘌呤交换因子
(GEF)生成激活的、GTP结合的GTP酶,具有精确的时间和定位,同时专门
与黏附分子、膜结构域和其他局部结构的相互作用
互动。全球环境基金/GTPase回路很复杂,有局部反馈,多个GEF控制一个
GTP酶,反之亦然。要剖析这种时空调节的电路,需要成像,而新的
可以从成像数据中剖析因果关系的分析技术。遵循PAR的意图-
19-158(生物工程研究拨款),我们建议利用有机技术进行多学科合作
化学、蛋白质工程、成像和计算机科学,极大地促进了信号转导
成像和分析。作为一个生物试验台,我们将探索环境基金-GTP酶相互作用在细胞中的作用
突起、单细胞迁移和集体迁移。我们将为全球环境基金制定一种可推广的方法
此外,我们还可以使用生物传感器,并改装我们成熟的GTPase生物传感器,以成像同一细胞中的全环基金和GTPase活性。
因为全球环境基金-GTP酶相互作用是异质的和复杂的,所以多路成像是必要的
量化它们的相对动力学。然而,在使用时,细胞行为的扰动尤其成问题
同一细胞中的两个生物传感器。因此,我们将开发新的生物传感器设计,大大减少细胞
微扰。即使是最精确的重叠分子激活成像也没有揭示原因
两性关系。因此,我们将采用格兰杰因果关系推理的框架,该框架最初是
专为金融市场分析而设计,从成像中提取因果联系和反馈交互
数据。要将格兰杰因果关系的现有概念转化为分析,需要许多步骤
时空分布的分子过程。最重要的是,我们将为
多变量时间序列模型中的Granger因果关系推断将捕捉空间关系,我们将
高维统计回归原理与控制论方法相结合进行估计
由强反馈耦合的变量之间的信息流。我们还将开发一部小说
一种在高维特征空间中保持数据的邻域拓扑的聚类方法
在细胞轮廓的欧几里得空间中识别信号微域。最后,为了测试和确认我们的
假设,我们将使用新的GEF的光激活和光抑制类似物以及GTP酶
生物传感器在观察一种蛋白质的同时控制另一种蛋白质。这项研究计划将生产生物传感器和
减少扰动、生物传感器/光遗传多路传输能力和图像分析/建模
阐明非线性时空受控信令的网络拓扑所需的方法
小路。所有工具都将高效地部署到社区。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Fine-grained, nonlinear registration of live cell movies reveals spatiotemporal organization of diffuse molecular processes.
- DOI:10.1371/journal.pcbi.1009667
- 发表时间:2022-12
- 期刊:
- 影响因子:4.3
- 作者:
- 通讯作者:
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Gaudenz Danuser其他文献
Gaudenz Danuser的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Gaudenz Danuser', 18)}}的其他基金
UTSW-UNC Center for Cell Signaling Analysis
UTSW-UNC 细胞信号分析中心
- 批准号:
10412148 - 财政年份:2022
- 资助金额:
$ 51.49万 - 项目类别:
UTSW-UNC Center for Cell Signaling Analysis
UTSW-UNC 细胞信号分析中心
- 批准号:
10705616 - 财政年份:2022
- 资助金额:
$ 51.49万 - 项目类别:
Integrated visualization, control, and analysis of GEF – GTPase networks in living cells
活细胞中 GEF – GTPase 网络的集成可视化、控制和分析
- 批准号:
10221568 - 财政年份:2021
- 资助金额:
$ 51.49万 - 项目类别:
Integrated visualization, control, and analysis of GEF – GTPase networks in living cells
活细胞中 GEF – GTPase 网络的集成可视化、控制和分析
- 批准号:
10379219 - 财政年份:2021
- 资助金额:
$ 51.49万 - 项目类别:
Imaging mechanisms of metastatic tumor formation in situ
原位转移性肿瘤形成的成像机制
- 批准号:
10374648 - 财政年份:2021
- 资助金额:
$ 51.49万 - 项目类别:
Imaging mechanisms of metastatic tumor formation in situ
原位转移性肿瘤形成的成像机制
- 批准号:
10684857 - 财政年份:2021
- 资助金额:
$ 51.49万 - 项目类别:
Imaging mechanisms of metastatic tumor formation in situ
原位转移性肿瘤形成的成像机制
- 批准号:
10491345 - 财政年份:2021
- 资助金额:
$ 51.49万 - 项目类别:
相似海外基金
Transcriptional assessment of haematopoietic differentiation to risk-stratify acute lymphoblastic leukaemia
造血分化的转录评估对急性淋巴细胞白血病的风险分层
- 批准号:
MR/Y009568/1 - 财政年份:2024
- 资助金额:
$ 51.49万 - 项目类别:
Fellowship
Combining two unique AI platforms for the discovery of novel genetic therapeutic targets & preclinical validation of synthetic biomolecules to treat Acute myeloid leukaemia (AML).
结合两个独特的人工智能平台来发现新的基因治疗靶点
- 批准号:
10090332 - 财政年份:2024
- 资助金额:
$ 51.49万 - 项目类别:
Collaborative R&D
Acute senescence: a novel host defence counteracting typhoidal Salmonella
急性衰老:对抗伤寒沙门氏菌的新型宿主防御
- 批准号:
MR/X02329X/1 - 财政年份:2024
- 资助金额:
$ 51.49万 - 项目类别:
Fellowship
Cellular Neuroinflammation in Acute Brain Injury
急性脑损伤中的细胞神经炎症
- 批准号:
MR/X021882/1 - 财政年份:2024
- 资助金额:
$ 51.49万 - 项目类别:
Research Grant
KAT2A PROTACs targetting the differentiation of blasts and leukemic stem cells for the treatment of Acute Myeloid Leukaemia
KAT2A PROTAC 靶向原始细胞和白血病干细胞的分化,用于治疗急性髓系白血病
- 批准号:
MR/X029557/1 - 财政年份:2024
- 资助金额:
$ 51.49万 - 项目类别:
Research Grant
Combining Mechanistic Modelling with Machine Learning for Diagnosis of Acute Respiratory Distress Syndrome
机械建模与机器学习相结合诊断急性呼吸窘迫综合征
- 批准号:
EP/Y003527/1 - 财政年份:2024
- 资助金额:
$ 51.49万 - 项目类别:
Research Grant
FITEAML: Functional Interrogation of Transposable Elements in Acute Myeloid Leukaemia
FITEAML:急性髓系白血病转座元件的功能研究
- 批准号:
EP/Y030338/1 - 财政年份:2024
- 资助金额:
$ 51.49万 - 项目类别:
Research Grant
STTR Phase I: Non-invasive focused ultrasound treatment to modulate the immune system for acute and chronic kidney rejection
STTR 第一期:非侵入性聚焦超声治疗调节免疫系统以治疗急性和慢性肾排斥
- 批准号:
2312694 - 财政年份:2024
- 资助金额:
$ 51.49万 - 项目类别:
Standard Grant
ロボット支援肝切除術は真に低侵襲なのか?acute phaseに着目して
机器人辅助肝切除术真的是微创吗?
- 批准号:
24K19395 - 财政年份:2024
- 资助金额:
$ 51.49万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Acute human gingivitis systems biology
人类急性牙龈炎系统生物学
- 批准号:
484000 - 财政年份:2023
- 资助金额:
$ 51.49万 - 项目类别:
Operating Grants














{{item.name}}会员




