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: 8913630
• 负责人: XUEDONG LIU
• 金额: $ 30.72万
• 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/8913630
• 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; Goals; Growth Factor; Hydrogels; Investigation; Kinetics; Life; MAP Kinase Gene; Measurement; Measures; Mechanics; Modeling; Molecular; Movement; Neoplasm Metastasis; Outcome; Pathway interactions; Play; Process; Property; Regulation; Role; Signal Transduction; Skin; Specific qualifier value; Staging; System; Systems Biology; Therapeutic; Tissues; Traction; Transforming Growth Factors; Wound Healing; Wounds and Injuries; analytical method; base; cell motility; cellular imaging; design; experience; improved; in vivo; insight; mathematical model; migration; network architecture; novel; programs; promoter; public health relevance; repaired; research study; 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.