Spatio-temporal dynamics of GEF-GTPase networks

GEF-GTPase 网络的时空动态

• 批准号: 9127980
• 负责人: Klaus M. Hahn
• 金额: $ 110.2万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9127980
• 关键词: Actins; Address; Adhesions; Apoptosis; Architecture; Back; Behavior; Biochemical; Biochemical Genetics; Biological Assay; Biosensor; Cadherins; Cell Adhesion Molecules; Cell Nucleus; Cell Polarity; Cell physiology; Cell surface; Cell-Cell Adhesion; Cell-Matrix Junction; Cells; Complex; Coupled; Cues; Cytokinesis; Cytoskeleton; DNA Damage; Data; Dependency; Disease; Eukaryotic Cell; Event; Family; Feedback; Genetic Transcription; Goals; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate; Guanosine Triphosphate Phosphohydrolases; Health; Heterogeneity; Human Genome; Hydrolysis; Image; Imagery; In Situ; Individual; Integral Membrane Protein; Integrins; Intercellular Junctions; Kinetics; Knowledge; Life; Light; Lipids; Location; Measures; Mechanics; Mediating; Methods; Microfilaments; Modeling; Molecular; Molecular Conformation; Network-based; Nuclear; Nuclear Envelope; Nucleotides; Pathway interactions; Phagocytosis; Play; Procedures; Process; Property; Protein Family; Proteins; Recruitment Activity; Regulation; Reporting; Resolution; Role; Signal Transduction; Signaling Molecule; Signaling Protein; Spatial Distribution; Specificity; Stimulus; Structure; System; Testing; Time; Work; base; cell behavior; cell motility; computerized tools; design; feeding; in vivo; innovative technologies; mathematical model; member; migration; network architecture; novel; novel strategies; polymerization; programs; receptor; research study; response; rho; rho GTP-Binding Proteins; tool

DESCRIPTION (provided by applicant): Rho family GTPases is ubiquitous molecular switches that control extraordinarily diverse cellular processes. They are activated by guanine nucleotide exchange factors (GEFs) that are roughly 5-fold more numerous than the GTPases themselves and integrate the many cellular inputs controlling GTPase function. GEFs and GTPases form complex networks that are constituted transiently and locally for specific purposes. Biochemical, genetic, molecular, and structural analyses have unraveled a great deal about these critically important pathways, but the most important functional property, their spatio-temporal regulation, can only be fully understood in the context of intact cells. This PPG brings together team members with diverse expertise to develop innovative technologies enabling the study of GEF/GTPase networks in vivo, computational tools to extract network architecture and signaling kinetics from imaging data, and in-depth knowledge of cell behaviors critically dependent on GEF/GTPase dynamics: (Project 1- Hahn) will deliver GEF biosensors based on designs addressing different GEF structural classes. In a collaborative effort with Sondek, expert in GEF structure, different biosensor designs will report GEF activation by specific upstream inputs, and activation of endogenous GEFs. (Project 2- Danuser) will develop the ability to simultaneously image and/or photomanipulate the activity of any pair of GEFs and GTPases, for high resolution studies of GEF/GTPase spatio-temporal coordination. New computational tools will combine data from different experiments to model large networks, and to extract network architecture and signaling kinetics from imaging data. These methods will be tested in studies of complex GEF-GTPase feedback interactions. (Project 3- Hall): This biologically focused project will extend our work to multicellular systems. We will focus on GEF activation in cell-cell junctions and cryptic lamellipodia, and identify GEFs regulating collective migration. (Project 4- Burridge) will address the role of GEF/GTPase netvvorks in mechanotransduction, exploring novel findings regarding the mechanical regulation of RhoA signaling at cell-matrix and cell-cell adhesions during initiation of protrusions, and in the nucleus.

描述（由申请人提供）：Rho家族GTPases是无处不在的分子开关，可控制多样化的细胞过程。它们被鸟嘌呤核苷酸交换因子（GEFS）激活，它们比GTPases本身多大约5倍，并整合了控制GTPase功能的许多细胞输入。 GEF和GTPases形成复杂的网络，这些网络是出于特定目的的瞬时和本地构成的。生化，遗传，分子和结构分析已经对这些至关重要的途径进行了很大的解释，但是最重要的功能特性，即它们的时空调节，只能在完整细胞的背景下才能完全理解。 This PPG brings together team members with diverse expertise to develop innovative technologies enabling the study of GEF/GTPase networks in vivo, computational tools to extract network architecture and signaling kinetics from imaging data, and in-depth knowledge of cell behaviors critically dependent on GEF/GTPase dynamics: (Project 1- Hahn) will deliver GEF biosensors based on designs addressing different GEF structural classes.在与GEF结构专家Sondek的合作努力中，不同的生物传感器设计将通过特定上游输入报告GEF激活，并激活内源性GEF。 （Project 2-Danuser）将发展能够同时对任何一对GEF和GTPases的活性进行图像和/或照相的能力，以进行GEF/GTPase时空协调的高分辨率研究。新的计算工具将结合来自不同实验的数据来建模大型网络，并从成像数据中提取网络体系结构和信号动力学。这些方法将在复杂的GEF-GTPase反馈相互作用的研究中进行测试。 （项目3-霍尔）：这个以生物学为中心的项目将我们的工作扩展到多细胞系统。我们将重点关注细胞 - 细胞连接和隐性薄片的GEF激活，并确定调节集体迁移的GEF。 （4-Burridge项目）将解决GEF/GTPase NetVorks在机械传输中的作用，并探讨有关在突发开始期间和细胞核中介入细胞 - 矩阵和细胞细胞粘附的RhoA信号传导机械调节的新发现。