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.

 描述：伤口愈合涉及生长因子和细胞间相互作用之间复杂的相互作用。 TGF-β 是已知参与体内伤口愈合的关键生长因子之一。 TGF-β 的分泌与组织修复的早期阶段一致，并促进集体细胞迁移。这一发现促使许多临床试验使用这种生长因子来治疗不愈合的伤口。尽管有很大的热情，但将其用作伤口促进剂并没有取得多大成功。使用生长因子进行伤口治疗的有限成功部分归因于伤口愈合生长因子以协调一致的方式并按顺序发挥作用来调节修复过程。对伤口愈合信号反应的时空调节的机制了解有限，加上缺乏定量建模和分析方法，阻碍了新的改进治疗策略的合理开发。我们的长期目标是开发一个定量框架来研究生长因子和力转导在正常和病理伤口愈合中的协同作用。尽管绝大多数研究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-β 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态的综合数学模型。我们假设：1) TGF-ß 信号传导提高迁移上皮片中 TACE 的水平； 2) TGF-ß通过机械相互作用的局部变化促进TACE活性升高； 3) TGF-β参与EGFR信号传导和TACE之间的正反馈回路，以维持伤口边界附近EGFR信号传导的升高。我们将使用系统生物学方法来研究我们的假设，该方法整合了动力学实验和数学模型，通过追求三个特定目标：1）识别信号基序，检测伤口的存在并控制 MAPK 动力学的空间受限激活，以响应 TGF-β 的整体治疗； 2) 确定机械力对 TGF-ß 伤口反应信号动态特性的影响； 3) 剖析并表征运动细胞中 TACE 活性和 EGFR 信号活性之间的正反馈机制。如果成功，拟议的研究将提供一个总体框架来分析生长因子和机械信号的协同作用。