Deciphering the network structure of signaling dynamics

解读信号动态的网络结构

• 批准号: 10112925
• 负责人: Chuan-Hsiang Huang
• 金额: $ 34.39万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10112925
• 关键词: Bar Codes; Biochemical; Biosensor; Cell Proliferation; Cell physiology; Cells; Characteristics; Chemicals; Chemotactic Factors; Chemotaxis; Clinical; Complex; Cytoplasm; Data; Development; Disease; Drug Combinations; EGF gene; Environment; Event; Feedback; Fluorescence Resonance Energy Transfer; Foundations; GTP-Binding Proteins; Goals; Guanosine Triphosphate Phosphohydrolases; Hela Cells; Image; Individual; Knowledge; MAP Kinase Gene; Malignant Neoplasms; Mechanics; Mediating; Metabolic Diseases; Metabolism; Methods; Modeling; Molecular; Monitor; PTK2 gene; Pathway Analysis; Pathway interactions; Pharmacology; Phosphatidylinositols; Phosphotransferases; Physiologic pulse; Play; Population; Property; Proteins; Refractory; Regulation; Reporting; Research; Role; SKOV3 cells; Series; Signal Transduction; Signaling Molecule; Signaling Protein; Stimulus; Structure; System; Techniques; Testing; Therapeutic Agents; Time; Travel; base; cancer cell; cell behavior; cell motility; cell type; developmental disease; experimental study; fascinate; insight; live cell imaging; migration; real time monitoring; response; sensor; small molecule inhibitor; spatiotemporal; success; tool

Project Summary/Abstract The signaling network involving Ras GTPases and their downstream effectors, particularly the PI3K and MAPK/ERK pathways, plays important roles in diverse cellular processes including proliferation, metabolism, migration, and survival. Derangements of the signaling network leads to diseases such as developmental anomalies, metabolic disorders, and cancer. Despite its clinical importance, targeting the Ras signaling network for disease treatment has been challenging due to an incomplete understanding of its complex regulation. Recent studies of the Ras signaling dynamics at the single-cell level revealed fascinating properties with important functional implications. In particular, we demonstrated that the Ras signaling network displays hallmarks of excitable systems such as stochastic activation, traveling waves, and all-or-none activation. The excitability of the Ras-PI3K-ERK signaling network plays important roles in cell motility and integration of chemical and mechanical stimuli that regulate cell proliferation. However, the overall structure of the Ras signaling network that encodes the excitable dynamics is not known. The purpose of this application is to analyze the structure of the Ras signaling network by systematically perturbing individual nodes and studying the effects on the excitable dynamics of the network. To this end we will develop a method based on fluorescent live cell imaging to simultaneously track a large number of signaling activities. We will use this method to monitor the excitable responses of ~30 signaling activities when each activity is pharmacologically inhibited. The effects of perturbations will provide insight into the regulatory relationship between the signaling activities. We will also carry out network analysis on different cell types to understand the basis of their distinct responses to small molecule inhibitors. These studies will pave the way for quantitative models containing sufficient details of the network to make accurate predictions of cellular responses.

项目摘要/摘要 涉及RAS GTPases及其下游效应子的信号网络，特别是 PI3K和MAPK/ERK途径，在包括 扩散，代谢，迁移和生存。信号网络引线的扰动 发育异常，代谢疾病和癌症等疾病。尽管有它 临床重要性，针对疾病治疗的RAS信号网络的临床重要性已经 由于对其复杂法规的不完全理解而挑战。最近的研究 在单细胞水平上的RAS信号传导动力学揭示了引人入胜的特性 功能含义。特别是，我们证明了RAS信号网络显示 可激发系统的标志，例如随机激活，行进波和无人机 激活。 RAS-PI3K-ERK信号网络的兴奋性在细胞中起着重要作用 调节细胞增殖的化学和机械刺激的运动和整合。 但是，编码可激发动力学的RAS信号网络的整体结构 不知道。该应用的目的是分析RAS信号的结构 通过系统地扰动单个节点并研究对兴奋的影响通过网络网络 网络的动力学。为此，我们将开发一种基于荧光活细胞的方法 成像以同时跟踪大量信号活动。我们将使用此方法 在每个活动为时 药理抑制。扰动的影响将为调节性提供深入的了解 信号活动之间的关系。我们还将对不同的网络分析 细胞类型了解它们对小分子抑制剂的不同反应的基础。这些 研究将为包含网络足够细节的定量模型铺平道路 对细胞反应进行准确的预测。