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ECM Remodeling in Excessive Fibroplasia

过度纤维增生的 ECM 重塑

基本信息

批准号：
7935388
负责人：
Paul David Benya
金额：
$ 39.48万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-07-01 至 2012-08-31
项目状态：
已结题

项目摘要

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.

该研究的长期目标是阐明细胞和分子基础伤口修复过程中形成过多的疤痕。疤痕疙瘩是肿瘤样皮肤疤痕，影响 10% 至 20% 的非洲裔、亚洲人和西班牙裔没有适当的治疗。在过去的资助期间，我们使用了 14 个新隔离的低通道 (<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 (PAI-1) 过度表达和胶原蛋白积累增加是内在的瘢痕疙瘩成纤维细胞的特征。我们还提供了新的、不同的因果关系证据 PAI-1表达与胶原蛋白积累的关系：腺病毒过表达以及 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胶原蛋白的积累分别升高。最后，由测试 PAI-1 的蛋白酶抑制和玻连蛋白结合突变体的能力诱导胶原蛋白积累，我们发现后者与野生型等效 PAI-1 和前者的有效性仅为 50% 左右。因此，PAI-1 利用蛋白酶抑制作为以及它的另一个功能是控制胶原蛋白的积累（Tuan et al., 2008, Am J 病理）。更新申请的目标是 1) 推进治疗策略靶向纤溶酶原激活剂抑制剂-1 (PAI-1) 来控制疤痕疙瘩胶原蛋白积累预防或治疗疤痕疙瘩的形成； 2）进一步明确和拓展机制 PAI-1 利用它来调节瘢痕疙瘩成纤维细胞中胶原蛋白的积累。