ECM REMODELING IN EXCESSIVE FIBROPLASIA

阐明过度瘢痕形成的细胞和分子基础 在伤口修复期间。目前的应用将集中在蜂窝 正常瘢痕成纤维细胞和瘢痕疙瘩成纤维细胞的分子差异 特别强调PAI/uPA系统的调节变化 在瘢痕疙瘩成纤维细胞中。从这项研究中获得的信息可能会导致 过度瘢痕防治方法的研究进展 在伤口修复过程中形成。调查人员将接近Long 通过阐明过度瘢痕的病理机制来实现学期目标 使用体外纤维增生症模型作为环境的形成 以正常瘢痕和纤维化为导向干扰基质重塑 成纤维细胞。调查人员已经证明了瘢痕疙瘩 成纤维细胞在纤维蛋白基质重塑中的变化 纤溶酶原激活物抑制物-1(PAI-1)和基础水平升高 和转化生长因子-β(TGF-b)刺激的水平 胶原蛋白。这些变化可能是在转化生长因子-b受体水平上介导的， 由于瘢痕疙瘩中转化生长因子-βI型受体的不同 成纤维细胞鉴定。调查人员假设a) PAI-1在瘢痕疙瘩成纤维细胞中的表达增加直接导致 瘢痕疙瘩有缺陷的纤维蛋白降解和持续性纤维增生，以及 B)增强了对转化生长因子-b的反应性，通过改变 受体特征，诱导瘢痕疙瘩PAI-1表达升高 细胞。调查人员将用四个具体的例子来检验这些假说 目标：特定目标1：表征一种基质重塑表型 适用于正常瘢痕和瘢痕疙瘩成纤维细胞。具体目标二.测试 UPA/PAI-1和uPA/PAI-1之间存在因果关系 操纵uPA/PAI表型引起纤维蛋白降解的急性变化 逆转录病毒在正常瘢痕成纤维细胞和瘢痕疙瘩成纤维细胞中的表达 将PAI-1/反义PAI-1转导入这些细胞。特定目标 三、确定是否存在直接因果关系 在特定改变的uPA/PAI-1表型和 随着时间的推移而发展的重塑的ECM。具体目标四.确定 瘢痕疙瘩成纤维细胞的转化生长因子-β受体及其配体的检测 结合或受体信号传递是导致这种增加的原因 瘢痕疙瘩成纤维细胞在该模型中合成纤溶酶原激活物-1和胶原。

To elucidate the cellular and molecular basis of excess scar formation during wound repair. The present application will focus on the cellular and molecular differences between normal scar and keloid fibroblasts with a special emphasis on the altered regulation of the PAI/uPA system in keloid fibroblasts. Information obtained from this study may lead to development of methods for prevention and treatment of excess scar formation during wound repair. The investigators will approach the long term goal by elucidating the pathologic mechanisms of excess scar formation using an in vitro fibroplasia model as an environment for perturbing matrix remodeling directed by normal scar and fibrotic fibroblasts. The investigators have demonstrated that keloid fibroblasts exhibit changes in fibrin matrix remodeling by expressing elevated levels of plasminogen activator inhibitor-1 (PAI-1) and basal and transforming growth factor-beta (TGF-b) stimulated-levels of collagen. These changes may be mediated at the TGF-b receptor level, since a difference in the TGF-b type I receptor profile in keloid fibroblasts was identified. The investigators hypothesize a) that increased expression of PAI-1 in keloid fibroblasts leads directly to defective fibrin degradation and persistent fibroplasia in keloids, and b) that increased responsiveness to TGF-b, mediated by an altered profile of receptors, induces this elevated PAI-1 expression in keloid cells. The investigators will test these hypotheses with four specific aims: Specific Aim 1: To characterize a matrix remodeling phenotype for normal scar and keloid fibroblasts. Specific Aim II. To test for the presence of a cause and effect relationship between uPA/PAI-1 and acute changes in fibrin degradation by manipulating uPA/PAI phenotypic expression in normal scar and keloid fibroblasts using retroviral transduction of PAI-1/antisense PAI-1 into these cells. Specific Aim III. To determine if a direct cause and effect relationship exists between a specifically altered uPA/PAI-1 phenotype and the nature of the remodeled ECM that develops over time. Specific Aim IV. To characterize TGF-b receptors from keloid fibroblasts and determine whether ligand binding or receptor signaling are responsible for the increased synthesis of PAI-1 and collagen by keloid fibroblasts in this model.