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。TGF-β是已知参与体内伤口愈合的关键生长因子之一。TGF-β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。尽管有很多热情，但它作为伤口促进剂的使用并没有太大的成功。将生长因子用于伤口治疗的有限成功可部分归因于伤口愈合生长因子以协调的方式和顺序作用以调节修复过程的事实。对创伤愈合信号应答的时空调控机制的理解有限，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。我们的长期目标是建立一个定量的框架来研究正常和病理性伤口愈合中生长因子和机械传导的协同作用。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。本申请的目的是定量评估TGF-β信号传导和机械应变的整合，并开发能够预测系统水平伤口愈合动力学的综合数学模型。我们假设：1）TGF-β信号传导提高了迁移性上皮片层中TACE的水平; 2）TGF-β通过机械相互作用的局部变化促进了TACE活性的提高; 3）TGF-β参与EGFR信号传导和TACE之间的正反馈回路，以维持伤口边缘附近升高的EGFR信号传导。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建模，通过追求三个具体目标：1）识别检测伤口存在并控制响应于TGF-β全面治疗的MAPK动力学的空间受限激活的信号基序; 2）确定机械力对TGF-β创伤响应信号传导的动力学性质的影响; 3）分析运动细胞中TACE活性与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，以分析生长因子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.