ECM Remodeling in Excessive Fibroplasia

这项研究的长期目标是阐明 在伤口修复过程中形成过多的疤痕。瘢痕疙瘩是一种肿瘤样的皮肤疤痕， 10%到20%的非洲裔、亚洲人和西班牙裔人没有适当的 治疗。在过去的资助期间，我们使用了14个新的隔离和低通道， （3）来自人类患者的正常和瘢痕疙瘩成纤维细胞株，并提供了新的 有证据表明（派-1）过度表达和胶原积累升高是内在的 瘢痕疙瘩成纤维细胞的特征。我们还提供了新的和不同的证据， 派-1表达与胶原积聚的关系：腺病毒 过表达和siRNA和shRNAmir抑制表明派-1产生 分别在正常和瘢痕疙瘩成纤维细胞中增加胶原积累。最后通过 测试派-1的蛋白酶抑制和玻连蛋白结合突变体， 诱导胶原蛋白积累，我们发现后者与野生型胶原蛋白积累是等效的， 派-1和前者只有~50%的有效性。因此，派-1利用蛋白酶抑制作用， 以及其控制胶原积累的另一功能（Tuan等人，2008年，美国《纽约时报》 Pathol）。更新申请的目标是：1）推进一种治疗策略， 靶向纤溶酶原激活物抑制剂-1（派-1）以控制瘢痕疙瘩胶原积聚 预防或治疗瘢痕疙瘩形成; 2）进一步定义和扩展 利用派-1调节瘢痕疙瘩成纤维细胞中的胶原积累。

The long term goal of the research is to elucidate the cellular and molecular basis of excess scar formation during wound repair. Keloids are tumor-like skin scars that affect 10 to 20% of people of African decent, Asians, and Hispanics without appropriate treatments. During the past funding period, we used 14 freshly isolated and low passages (<3) strains of normal and keloid fibroblasts from human patients and provided new evidence that (PAI-1) overexpression and elevated collagen accumulation are intrinsic features of keloid fibroblasts. We also provided new and different evidence of a causal relationship between PAI-1 expression and collagen accumulation: adenoviral overexpression and siRNA and shRNAmir suppression demonstrate that PAI-1 produces elevated collagen accumulation in normal and keloid fibroblasts, respectively. Finally, by testing protease-inhibitory and vitronectin-binding mutants of PAI-1 for their capacity to induce collagen accumulation, we found that the latter was equipotent with wild-type PAI-1 and the former was only ~50% effective. Thus, PAI-1 utilizes protease inhibition as well as another of its functions to control collagen accumulation (Tuan et al., 2008, Am J Pathol). The goals of the renewal application are 1) to advance a therapeutic strategy that targets plasminogen activator inhibitor-1 (PAI-1) to control keloid collagen accumulation and prevent or treat keloid formation; 2) to further define and expand the mechanisms utilized by PAI-1 to regulate collagen accumulation in keloid fibroblasts.