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：
9414041
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/9414041
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 Human Hydrolysis Image Information Theory Injury Kinetics Knowledge Lead 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 Wound Healing 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 public health relevance response spatiotemporal success synergism therapy development tool uptake wound

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（由申请人提供）：角膜伤口可导致疤痕、混浊和随后的视力丧失。包括细胞外核苷酸和生长因子在内的多种生化信号在伤口诱导的分子特性的激活中发挥着关键作用。标志着旨在延长自然愈合过程的治疗方法的发展，以尽量减少损伤引起的视力丧失的危险，但是，这些治疗方法仅取得有限的成功，因为缺乏对这些调节的详细定量机制的了解。旁分泌信号分子阻碍了对当前疗法的严格评估和下一代定量系统药理学治疗方法的开发，这项工作的目标是确定控制两种关键旁分泌信号分子时空传播的调节机制：ATP。和 HB-EGF。每个在伤口愈合程序的激活中都发挥着重要作用，该提案将利用我们最近开发的基于微流体的新型伤口平台，能够高度控制上皮伤口。我们将使用新设备与多种计算方法协同来剖析控制伤口传播的旁分泌信号调节网络。具体目标是：（1）阐明控制初始 ATP 信号传播的机制（2）剖析负责 Erk 通路激活的空间传播的机制。 (3) 确定旁分泌信号在降低 Erk 通路激活噪声中的功能在目标 1 和 2 中，我们将构建并独立校准将细胞间 ATP 和 HB-EGF 动力学与细胞内动力学相结合的多尺度组织水平模型。该模型将用于测试有关控制 ATP 和 HB-EGF 信号时空传播以激活伤口反应信号传导的机制的多种假设。 3 我们将使用信息论方法来分析测试已识别的机制如何有助于生成强大的 Erk 激活空间分布。这些目标的成功完成将弥补调节 Erk 激活的复杂机制的重要知识差距。我们将构建并通过实验证实的预测数学模型将为未来疗法的设计提供重要工具，旨在增强现有的伤口愈合计划，以防止角膜损伤引起的视力丧失。