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.

描述（由适用提供）：角膜伤口可能导致疤痕，欺凌和随后的视力丧失。几种生化信号，包括细胞外核苷酸和生长因子在伤口愈合程序的激活中起着关键作用。伤口引起信号的分子身份的发现促使旨在延长自然愈合程序的疗法的发展，以最大程度地减少受伤引起的视力丧失的危险。但是，这些治疗方法的成功只有有限的成功。缺乏对这些旁分泌信号分子调节的详细定量机械理解，可以阻止对当前疗法的关键评估和下一代定量系统药理学治疗方法的发展。这项工作的目的是确定控制两个关键的旁分泌信号分子的空间 - 周期传播的调节机制：ATP和HB-EGF。每个人在伤口愈合程序的激活中起着至关重要的作用。该建议将利用我们最近开发的基于微流体的新型逻辑平台。新设备可以实现高度控制的上皮单层生活，而无需任何流体混合，从而生成了CA2+和ERK途径的时空传播的实时数据。我们将使用多种计算方法使用Synergy的新设备来剖析控制伤口诱导信号的传播的旁分泌信号调节网络。具体目的是：（1）阐明控制初始ATP信号传播的机制。（2）剖析负责ERK途径激活空间传播的机制。（3）确定旁分泌信号在减少ERK途径激活中的噪声方面的功能。在目标1和2中，我们将构建并独立校准多尺度的组织级模型，这些模型将细胞间ATP和HB-EGF动力学与细胞内CA2+和ERK途径激活的动力学结合在一起。这些模型将用于测试有关控制ATP和HB-EGF信号的空间传播机制的多个假设，以激活粉粉响应信号传导。在AIM 3中，我们将使用信息理论方法来分析测试确定的机制如何有助于生成ERK激活的稳健空间分布。这些目标的成功完成将缩小有关调节伤口愈合程序激活的复杂机制的重要知识差距。我们将构建和实验证实的预测性数学模型将为未来疗法设计提供重要的工具，旨在增强现有的伤口愈合计划，以防止因角膜损伤而导致视力丧失。