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: 9768888
• 负责人: XUEDONG LIU
• 金额: $ 36.53万
• 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 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9768888
• 关键词: Affect; 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 Force Microscopy; 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; non-healing wounds; 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：伤口愈合涉及生长因子和细胞相互作用之间的复杂相互作用。 TGF-ß是已知与体内伤口愈合有关的关键生长因子之一。 TGF-ß分泌与组织修复的早期阶段相吻合，并促进集体细胞迁移。这种关系促使许多使用该生长因子来治疗非治疗伤口的临床试验。尽管热情充满热情，但它用作伤口促进者并没有太大的成功。使用伤口疗法的生长因子的成功有限可以部分归因于以下事实：伤口愈合生长因子以一致的方式起作用，并顺序调节修复过程。对伤口愈合信号反应的空间时间调节的机械理解有限，再加上缺乏定量建模和分析方法，这阻碍了新的改进治疗策略的合理发展。我们的长期目标是开发一个定量框架，以研究生长因子的一致作用和在正常和病理伤口愈合中的机械翻译。尽管绝大多数投资都描述了伤口愈合细胞对生化信号的反应，但越来越清楚的是机械力也可以作为信号转导的输入。该应用的目的是定量评估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级伤口愈合动力学的综合数学模型。我们假设：1）通过机械相互作用的局部变化，TGF-ß信号传递升高的TACE活性升高； 3）TGF-ß参与EGFR信号和TACE之间的积极反馈回路，以维持伤口边界附近的EGFR信号。我们将使用一种系统生物学方法来研究我们的假设，该方法通过追求三个特定目的来整合动力学实验和数学建模：1）确定检测伤口的存在并控制MAPK动力学的空间约束激活，以响应TGF-ß的全局处理，以响应MAPK动力学的空间约束激活； 2）确定机械力对TGF-β伤口反应信号的动态特性的影响； 3）剖析和表征运动细胞中TACE活性和EGFR信号活性之间阳性反馈的机制。如果成功，拟议的研究将提供一个一般框架，以分析生长因素和机械信号的协同作用。