Quantitative Analysis of Mechanochemical Signaling in Wound Response

 描述：伤口愈合涉及生长因子和细胞-细胞相互作用之间的复杂相互作用。转化生长因子是体内已知参与创面愈合的关键生长因子之一。转化生长因子的分泌与组织修复的早期阶段相吻合，并促进集体细胞的迁移。这一发现已经促使许多临床试验使用这种生长因子来治疗不可愈合的伤口。尽管有很多热情，但将其用作伤口促进剂并不是很成功。将生长因子用于创伤治疗的有限成功可以部分归因于这样一个事实，即伤口愈合生长因子以协调的方式和顺序地作用于调节修复过程。创伤愈合信号反应的时空调控机制认识有限，再加上缺乏定量的建模和分析方法，阻碍了新的改进治疗策略的合理发展。我们的长期目标是建立一个定量的框架来研究生长因子和机械转导在正常和病理性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。这项应用的目的是定量评估转化生长因子-？？信号和机械应变的整合，并开发一个全面的数学模型，能够预测系统级的伤口愈合动力学。我们假设：1)在移行的上皮片中，转化生长因子-B信号上调了TACE的水平；2)转化生长因子-B通过局部机械相互作用的改变促进了血管紧张素转换酶活性的升高；3)转化生长因子-B在EGFR信号和TACE之间形成了一个正反馈循环，以维持创面边缘附近升高的EGFR信号。我们将使用结合动力学实验和数学建模的系统生物学方法来验证我们的假说，以追求三个具体目标：1)确定检测创伤存在的信号基序，并控制MAPK动力学在整体治疗后受空间限制的激活；2)确定机械力对转化生长因子β对创伤反应信号的动态特性的影响；3)解剖并表征运动细胞中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一般框架，以分析生长因素和机械信号的协同作用。

 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.