Fibroblast Differentiation in Wound Healing

组织收缩是伤口闭合的组成部分;然而，过度或异常的组织收缩会导致伤口愈合。 组织可导致病理性挛缩、组织变形和组织功能丧失， 美国的问题。这个项目的长期目标是了解细胞基础 潜在的伤口收缩和组织挛缩，通过研究的形成和功能， 肌成纤维细胞肌成纤维细胞是表达平滑肌α-肌动蛋白（SMAA）的特化成纤维细胞 并组装可收缩的结构元件作为其产生收缩力的能力的一部分 负责组织收缩细胞外基质的机械性质在细胞外基质中是至关重要的。 调节SMAA表达以及其他SM特异性细胞骨架蛋白和肌成纤维细胞形成 和功能这些结果导致了一系列关于机械调节的新假说， 肌成纤维细胞的形成和功能：（i）机械调节SM特异性细胞骨架表达， 肌成纤维细胞是由肌动蛋白动力学的变化介导的;（ii）肌心蛋白相关转录因子A （MRTF-A）通过易位将肌动蛋白动力学中的机械调节变化与基因表达偶联 从细胞质肌动蛋白到细胞核;（iii）MRTF-A激活SM特异性细胞骨架蛋白的一个子集， （iv）MRTF-A激活这一SM特异性细胞骨架蛋白亚群， 蛋白质负责肌成纤维细胞的形成和功能。我们将测试这些假设， 使用组织培养和动物创伤模型，其中对不同机械环境的反应可以 接受检查。此外，我们将使用siRNA敲低MRTF-A和SMAA的表达，以确定 它们在肌成纤维细胞形成和功能中的作用。与公共卫生的相关性：为了控制伤口 愈合和病理性挛缩的破坏性影响，调节形成和 肌成纤维细胞的功能。这项提案将测试肌成纤维细胞的形成和功能是否可以被 通过靶向特定的信号传导途径和转录调控事件进行调节， 在动物模型中对伤口愈合和组织挛缩的影响。这项研究将为以下方面提供基础： 将有关肌成纤维细胞形成和功能的基础科学发现转化为新的 控制伤口愈合和病理性挛缩的治疗方法。

Tissue contraction is an integral part of wound closure; however, excessive or abnormal contraction of tissues can lead to pathological contractures, tissue deformation and loss of tissue function, all major health problems in the United States. The long-term goal of this project is to understand the cellular basis underlying wound contraction and tissue contracture by studying the formation and function of the myofibroblast. Myofibroblasts are specialized fibroblasts that express smooth muscle alpha-actin (SMAA) and assemble contractile structural elements as part of their ability to generate the contractile force responsible for tissue contraction. The mechanical properties of the extracellular matrix are critical in regulating SMAA expression, as well as other SM-specific cytoskeletal proteins, and myofibroblast formation and function. These results have led to a series of novel hypothesis regarding mechano-regulation of myofibroblast formation and function: (i) mechano-regulation of the SM-specific cytoskeletal expression in myofibroblasts is mediated by changes in actin dynamics; (ii) myocardin-related transcription factor A (MRTF-A) couples mechano-regulated changes in actin dynamics with gene expression by translocating from cytoplasmic actin to the nucleus; (iii) MRTF-A activates a subset of SM-specific cytoskeletal proteins, in addition to SMAA, in myofibroblasts; (iv) MRTF-A activation of this subset of SM-specific cytoskeletal proteins is responsible for the formation and function of myofibroblasts. We will test these hypotheses by use of tissue culture and animal wound models in which response to different mechanical environments can be examined. In addition, we will knock down expression of MRTF-A and SMAA using siRNA to determine their role in myofibroblast formation and function. Relevance to Public Health: In order to control wound healing and the devastating effects of pathological contractures it is essential to regulate the formation and function of the myofibroblast. This proposal will test whether myofibroblast formation and function can be regulated by targeting specific signaling pathways and transcriptional regulatory events and the effect this has on wound healing and tissue contracture in animal models. This study will provide the basis for translating basic science findings on the myofibroblast formation and function into the development of novel therapeutic approaches to control wound healing and pathologic contractures.