ECM Remodeling in Excessive Fibroplasia

这项研究的长期目标是阐明糖尿病的细胞和分子基础。 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皮肤疤痕，影响 10%到20%的非洲体面人、亚洲人和西班牙人没有适当的 治疗。在过去的资助期间，我们使用了14个新隔离的低通道 (&lt；3)株正常人和瘢痕疙瘩成纤维细胞，并提供了新的 有证据表明(PAI-1)过表达和胶原沉积增加是固有的 瘢痕疙瘩成纤维细胞的特征。我们还提供了新的和不同的因果关系证据。 纤溶酶原激活物-1表达与胶原堆积的关系：腺病毒 过度表达和siRNA和shRNAmir抑制表明PAI-1产生 正常成纤维细胞和瘢痕疙瘩成纤维细胞中的胶原堆积分别增加。最后，通过 检测PAI-1的蛋白水解酶抑制突变体和玻璃体连接蛋白结合突变体的能力 诱导胶原蛋白堆积，我们发现后者与野生型相当 PAI-1，前者的有效率仅为50%。因此，PAI-1利用蛋白酶抑制作为 以及它的另一个控制胶原堆积的功能(Tuan等人，2008，Am J 帕索尔)。续签申请的目标是1)推进一种治疗策略， 以纤溶酶原激活物抑制物-1为靶点控制瘢痕疙瘩胶原堆积 并预防或治疗瘢痕疙瘩的形成；2)进一步明确和拓展其作用机制 被PAI-1用来调节瘢痕疙瘩成纤维细胞中胶原的积累。

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.