Fibroblast Differentiation in Wound Healing

伤口愈合中的成纤维细胞分化

• 批准号: 7747932
• 负责人: JAMES J TOMASEK
• 金额: $ 26.68万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7747932
• 关键词: Actins; Animal Model; Animals; Basic Science; Binding; Cell Nucleus; Cell surface; Complex; Contracts; Contracture; Coupled; Couples; Cytoskeletal Proteins; Cytoskeleton; Development; Elements; Environment; Event; Extracellular Matrix; F-Actin; Fibroblasts; Figs - dietary; Focal Adhesions; Funding; G Actin; Gene Expression; Goals; Granulation Tissue; Health; In Vitro; Indium; Laboratories; Lead; Mechanical Stress; Mechanics; Mediating; Microfilaments; Modeling; Myofibroblast; Myosin Heavy Chains; Nuclear Translocation; Pathologic; Play; Property; Proteins; Public Health; Regulation; Research Personnel; Role; Series; Serum Response Factor; Signal Pathway; Small Interfering RNA; Smooth Muscle; Smooth Muscle Actin Staining Method; Smooth Muscle Myocytes; Smooth Muscle Myosins; Stress Fibers; Testing; Tissues; Translating; United States; Wound Healing; alpha Actin; base; calponin-h1; factor A; in vivo; knock-down; loss of function; myocardin; novel; novel therapeutic intervention; programs; promoter; response; tissue culture; transcription factor; wound

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.

组织收缩是伤口闭合的组成部分。但是，收缩过多或异常 组织可以导致病理染色，组织变形和组织功能的丧失，所有主要健康 在美国的问题。该项目的长期目标是了解细胞基础 通过研究 肌纤维细胞。肌纤维细胞是表达平滑肌α-肌动蛋白（SMAA）的专门成纤维细胞 并组装收缩结构元素，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能至关重要 调节SMAA表达以及其他SM特异性细胞骨架蛋白和肌纤维细胞的形成 和功能。这些结果导致了一系列有关机械调节的新假设 肌纤维细胞的形成和功能：（i）SM特异性细胞骨架表达的机械调节 肌纤维细胞是由肌动蛋白动力学变化介导的。 （ii）与心肌相关的转录因子A （MRTF-A）夫妻通过易位通过基因表达的肌动蛋白动力学的机械调节变化 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子集 在肌纤维细胞中附加SMAA； （iv）SM特异性细胞骨架的MRTF-A激活 蛋白质负责肌纤维细胞的形成和功能。我们将通过 使用组织培养和动物伤口模型，其中对不同机械环境的反应可以 被检查。此外，我们将使用siRNA击倒MRTF-A和SMAA的表达来确定 它们在肌纤维细胞形成和功能中的作用。与公共卫生有关：为了控制伤口 治愈和病理染色的毁灭性影响，必须调节形成和 肌纤维细胞的功能。该建议将测试肌纤维细胞形成和功能是否可以 通过针对特定的信号通路和转录调节事件来调节，效果 在动物模型中具有伤口愈合和组织染色。这项研究将为 将有关肌纤维细胞形成和功能的基础科学发现转化为新颖的发展 控制伤口愈合和病理肾上腺的治疗方法。