Quantitative Analysis of Mechanochemical Signaling in Wound Response

伤口反应中机械化学信号的定量分析

• 批准号: 9353292
• 负责人: XUEDONG LIU
• 金额: $ 38.44万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-14 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9353292
• 关键词: Affect; Atomic Force Microscopy; Biochemical; Biological; Biosensor; Cell Communication; Cells; Clinical Trials; Complex; Coupled; Development; Epidermal Growth Factor Receptor; Epithelial; Event; Feedback; Fluorescence Resonance Energy Transfer; Genetic Transcription; Goals; Growth Factor; Hydrogels; Investigation; Kinetics; MAP Kinase Gene; Measurement; Measures; Mechanics; Modeling; Molecular; Movement; Neoplasm Metastasis; Outcome; Pathologic; Pathway interactions; Play; Process; Property; Regulation; Role; Signal Transduction; Skin; Specific qualifier value; System; Systems Biology; Therapeutic; Tissues; Traction; Transforming Growth Factor beta; Transforming Growth Factors; Wound Healing; Wounds and Injuries; analytical method; base; cell motility; design; experience; experimental study; improved; in vivo; insight; live cell imaging; mathematical model; mechanical force; mechanotransduction; migration; network architecture; novel; programs; promoter; public health relevance; repaired; response; spatiotemporal; success; tissue repair; tool; tumor progression; wound

 DESCRIPTION: Wound healing involves complex interplay between growth factors and cell-cell interactions. TGF-ß is one of the key growth factors that is known to be involved in wound healing in vivo. TGF-ß secretion coincides with the early stages of tissue repair and promotes collective cell migration. This revelation has prompted numerous clinical trials using this growth factor to treat nonhealing wounds. Despite much enthusiasm, there is not much success with its use as a wound promoter. The limited success using growth factors for wound therapies can in part be attributed to the fact that wound healing growth factors act in a concerted manner and in sequence to regulate the repair process. Limited mechanistic understanding of the spatiotemporal regulation of wound healing signaling response, coupled with the lack of quantitative modeling and analytical methods, has hampered the rational development of new improved therapeutic strategies. Our long-term goal is to develop a quantitative framework to investigate concerted action of growth factors and mechanotransduction in normal and pathological wound healing. Although the vast majority of investigations describe wound healing cellular responses to biochemical signals, it is becoming increasingly clear that mechanical force can also serve as an input for signal transduction. The objective of this application is to quantitatively assess integration of TGF-ß signaling and mechanical strain and develop a comprehensive mathematical model that is able to predict systems-level wound healing dynamics. We hypothesize: 1) TGF-ß signaling elevates the levels of TACE in migrating epithelial sheet; 2) TGF-ß promotes elevated TACE activity through local changes in mechanical interactions; 3) TGF-ß engages a positive feedback loop between EGFR signaling and TACE to sustain elevated EGFR signaling near a wound's border. We will investigate our hypothesis using a systems biology approach that integrates kinetic experiments and mathematical modeling by pursuing three specific aims: 1) Identify signaling motifs that detect the presence of a wound and control the spatially constrained activation of MAPK dynamics in response to global treatment of TGF-ß; 2) Determine the effect of mechanical force on the dynamic properties of wound response signaling by TGF-ß; 3) Dissect and characterize the mechanisms of positive feedback between TACE activity and EGFR signaling activity in motile cells. If successful, the proposed studies will provide a general framework to analyze concerted actions of growth factors and mechanical signals.

 描述：众所周知，康复的生长和细胞孤独感之间的相互作用。伤口疗法的因素可以归因于伤口愈合因子以一种协同的方式起作用，并依次归因于常规过程。 M. Ethods阻碍了新的改进的治疗策略的合理发展。 TROSEDUCTION IS ISS定量评估TGF-ß信号传导和机械应变的整合，并开发一个能够预测系统TEMS的数学模型模型 - 级别的伤口愈合动力学：1）TGF-ß信号提升迁移上皮纸的表格水平； 2）通过机械相互作用的局部变化，TACE活动； 3）EGFR信号之间的正反馈循环，以维持EGFR信号的升高。通过追求三个特定的AM进行建模：1）识别信号的存在，并控制MAPK动力学的空间解释，以响应TGF-ß）RCE的全局处理）解剖和表征运动细胞中转弯和EGFR信号活性之间的正反馈机制。