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Deciphering the network structure of signaling dynamics

解读信号动态的网络结构

基本信息

批准号：
10589106
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
项目类别：
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/10589106
关键词：
Bar Codes Biochemical Biosensor Cell Nucleus Cell Proliferation Cell physiology Cells Characteristics Chemicals Chemotactic Factors Chemotaxis Clinical Complex Cytoplasm Cytoskeleton 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 Mediating Metabolic Diseases Metabolism Methods Modeling Molecular Monitor PIK3CG gene PTK2 gene Pathway Analysis Pathway interactions Phosphatidylinositols Phosphotransferases Physiologic pulse Play Population Proliferating 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 cancer cell cell behavior cell motility cell type developmental disease experimental study fascinate insight live cell imaging mechanical stimulus migration pharmacologic real time monitoring response self organization sensor small molecule inhibitor spatiotemporal success tool

项目摘要

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.

项目总结/文摘