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The Spread of Noisy Information in Corneal Epithelial Wound Response Signaling

角膜上皮伤口反应信号中噪声信息的传播

基本信息

批准号：
9378292
负责人：
Roy Wollman
金额：
$ 36.59万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9378292
关键词：
ATP Hydrolysis Biochemical Biological Assay Biosensor Blindness Cell Density Cells Cicatrix Coculture Techniques Communication Complement Complex Computer Simulation Cornea Corneal Injury Data Development Devices Diffusion Dissection Epidermal Growth Factor Epithelial Epithelium Fluorescence Resonance Energy Transfer Future Generations Glean Goals Growth Factor Gene Healed Health Human Hydrolysis Image Imaging technology Information Theory Injury Kinetics Knowledge Lead Life Liquid substance MAP Kinase Gene Manuscripts Measurement Microfluidic Microchips Microfluidics Modeling Molecular Multiple Trauma Noise Nucleotides Paracrine Communication Pathway interactions Pharmacology Play Process Reaction Regulation Role Science Signal Transduction Signaling Molecule Site Spatial Distribution System Technology Testing Therapeutic Time Tissues Vision Work base corneal epithelium design extracellular feeding hazing healing insight mathematical methods mathematical model monolayer multi-scale modeling next generation novel novel therapeutics paracrine prevent programs response success therapy development tool uptake wound wound healing

项目摘要

DESCRIPTION (provided by applicant): Cornea wounds can lead to scarring, hazing, and subsequent vision loss. Several biochemical signals, including extracellular nucleotides and growth factors play key roles in activation of wound healing programs. The discoveries of the molecular identities of wound induced signals prompted the development of therapies that aim to prolong the natural healing programs in order to minimize the danger of injury induced vision loss. However, these therapeutic approaches had only limited success. The lack of a detailed quantitative mechanistic understanding of the regulation of these paracrine signaling molecules prevents the critical assessment of current therapies and the development of the next generation of quantitative systems pharmacology therapeutic approaches. The goal of this work is to determine the regulatory mechanism that controls the spatio-temporal propagation of two key paracrine signaling molecules: ATP and HB-EGF. Each plays an essential role in the activation of wound healing programs. This proposal will capitalize on a novel microfluidics-based wounding platform we recently developed. The new device enables highly controlled wounding of epithelial monolayers without any fluid mixing and thereby generates real-time data of the spatio-temporal propagation of the Ca2+ and Erk pathways. We will use the new device in synergy with multiple computational approaches to dissect the paracrine signaling regulatory network that controls the propagation of wound induced signals. The specific aims are: (1) Elucidate the mechanism that controls the spread of initial ATP signals. (2) Dissect the mechanisms responsible for the spatial propagation of Erk pathway activation. (3) Determine the function of paracrine signals in reducing the noise in Erk pathway activation. In aims 1 and 2 we will construct and independently calibrate multi-scale tissue-level models that combine intercellular ATP and HB-EGF dynamics with intracellular the kinetics of Ca2+ and Erk pathway activation. The models will be used to test multiple hypotheses on the mechanism that controls the spatio-temporal propagation of ATP and HB-EGF signals to activate wound response signaling. In aim 3 we will use an information-theory approach to analyze test how the identified mechanisms contribute to the generation of a robust spatial distribution of Erk activation. The successful completion of these aims will close an important knowledge gap on the complex mechanism that regulates the activation of wound healing programs. The predictive mathematical models that we will construct and experimentally corroborate will provide an important tool in the design of future therapies that aim to augment existing wound healing programs to prevent vision loss due to corneal injury.