Evaluation of a novel pro-fibrotic regulatory pathway in the skin

项目概要： 对组织损伤的理想反应是再生，完全恢复正常组织 架构不幸的是，成熟的皮肤通常通过修复过程愈合，导致形成 疤痕组织而不是正常组织。除了与疤痕相关的美容问题，疤痕组织 比正常皮肤更脆弱，功能上有缺陷。有趣的是，在胚胎的早期阶段， 胎儿的皮肤在发育过程中能够愈合，不留疤痕。我们使用小鼠胎儿伤口愈合模型， 比较胚胎第15天（E15）产生的再生无瘢痕伤口和纤维化瘢痕形成伤口， 在胚胎第18天（E18）产生的伤口。我们的实验室最近完成了 证明糖蛋白胎球蛋白-A（FetA）在E18成纤维细胞中以显著更高的水平存在， E18皮肤和E18伤口与其E15对应物相比。初步数据还表明， E15胎儿伤口中的FetA破坏了无瘢痕愈合过程。这里提出的研究将测试 FetA刺激成纤维细胞和促进瘢痕形成的能力。因为FetA已经被证明可以与 并激活脂肪细胞中的TLR 4，其他TLR 4激动剂已被证明可以刺激成纤维细胞，我们将 还探索TLR 4活化作为FetA刺激成纤维细胞活化和瘢痕形成的潜在机制 组织生产。 拟议研究的中心假设是，FetA刺激疤痕组织的产生， 成纤维细胞中的TLR 4依赖性的方式。为检验这一假设，提出了以下具体目标： 1 -检查FetA对培养的真皮成纤维细胞的影响;目的2 -确定FetA是否促进瘢痕形成 体内形成。 该应用基于我们实验室产生的新数据，表明FetA参与瘢痕形成 阵关于FetA在皮肤中的功能以及FetA对成纤维细胞/瘢痕的影响知之甚少 没有检查过形成。因此，这项工作是重要的，因为它将提供重要的新的 科学信息。这些研究有可能通过建立FetA介导的TLR 4来影响该领域 激活作为一种新的机制途径参与功能失调，衰弱疤痕的形成。

PROJECT SUMMARY: The ideal response to tissue injury is regeneration, with the complete restoration of normal tissue architecture. Unfortunately, mature skin generally heals through a repair process which results in the formation of scar tissue instead of normal tissue. In addition to the cosmetic concerns associated with scars, scar tissue is weaker than normal skin and is functionally defective. Interestingly, at early stages of embryonic development, fetal skin is able to heal without a scar. We use a mouse model of fetal wound healing to compare regenerative, scarless wounds generated at embryonic day 15 (E15) and fibrotic, scar-forming wounds generated at embryonic day 18 (E18). Our lab has recently completed preliminary studies demonstrating that the glycoprotein Fetuin-A (FetA) is present at significantly higher levels in E18 fibroblasts, E18 skin, and E18 wounds compared to their E15 counterparts. Preliminary data also suggest that introduction of FetA into E15 fetal wounds disrupts the scarless healing process. The studies proposed here will test the ability of FetA to stimulate fibroblasts and promote scar formation. Because FetA has been shown to bind to and activate TLR4 in adipocytes and other TLR4 agonists have been shown to stimulate fibroblasts, we will also explore TLR4 activation as a potential mechanism by which FetA stimulates fibroblast activation and scar tissue production. The central hypothesis of the proposed studies is that FetA stimulates the production of scar tissue by fibroblasts in a TLR4-dependent manner. The following specific aims are proposed to test the hypothesis: Aim 1 – Examine the effects of FetA on cultured dermal fibroblasts; Aim 2 – Determine whether FetA promotes scar formation in vivo. This application is based on novel data generated by our lab suggesting that FetA is involved in scar formation. Very little is known about the function of FetA in the skin and the effects of FetA on fibroblasts/scar formation have not been examined. Therefore, this work is significant because it will provide important new scientific information. The studies have the potential to impact the field by establishing FetA-mediated TLR4 activation as a new mechanistic pathway involved in the formation of dysfunctional, debilitating scars.