Understanding the role of VEGF in scar formation

项目概要： 伤口修复过程中的并发症，包括过度或异常疤痕的形成 形成，影响数百万患者，并导致大量的医疗保健费用。疤痕组织阻碍正常 皮肤功能，并可能产生严重的心理社会后果。限制疤痕组织数量的能力 在受伤或外科手术后形成的，将是一个重大的临床进步， 对患者的巨大影响。为了开发新的治疗方法来对抗疤痕，一种更精确的 需要了解调节疤痕形成的机制。 越来越多的证据表明，促血管生成生长因子血管 内皮生长因子-A（VEGF）促进瘢痕形成。然而，几乎没有做什么来剖析 VEGF促进瘢痕形成的机制。我们的初步数据表明，成纤维细胞， 负责瘢痕形成的成纤维细胞表达VEGF受体，培养的成纤维细胞直接对VEGF应答。 因此，除了调节伤口血管生成外，VEGF还可能直接刺激血管生成。 通过真皮成纤维细胞中VEGFR-1和/或VEGFR-2的信号传导形成瘢痕。 基于VEGF促进瘢痕形成的证据以及初步数据， 表明VEGF受体存在于真皮成纤维细胞上并且这些细胞可以对VEGF产生应答， 所提出的研究的中心假设是VEGF通过直接作用促进瘢痕组织沉积， 刺激真皮成纤维细胞。为了检验这一假设，将实现以下具体目标： 探讨VEGF对体外成纤维细胞功能的影响;目的2 -确定VEGF对成纤维细胞功能的影响。 在体内发挥作用。 尽管有越来越多的证据表明VEGF调节瘢痕形成，但还没有详细的机制研究。 被执行。在这里，新的小鼠模型将用于解决这一知识差距， VEGF对成纤维细胞的直接作用，以及VEGF促进瘢痕形成的机制。 这些研究确定的机制可能超出伤口诱导的瘢痕形成， 并有可能在调节皮肤和其他器官的纤维化中发挥作用。

PROJECT SUMMARY: Complications in the wound repair process, including the formation of excessive or abnormal scar formation, affect millions of patients and result in substantial health care costs. Scar tissue impedes normal skin function and can have severe psychosocial consequences. The ability to limit the amount of scar tissue that forms following injury or surgical procedures would be a major clinical advance that would have a tremendous impact on patients. In order to develop novel therapies to combat scarring, a more precise understanding of the mechanisms that regulate scar formation is needed. A growing body of evidence is emerging suggesting that the pro-angiogenic growth factor vascular endothelial growth factor-A (VEGF) promotes scar formation. However, little has been done to dissect the mechanisms by which VEGF contributes to scarring. Our preliminary data suggest that fibroblasts, the cell type responsible for scar formation, express VEGF receptors and that cultured fibroblasts respond directly to VEGF. Therefore, it is possible that in addition to regulating wound angiogenesis, VEGF may also directly stimulate to scar formation by signaling through VEGFR-1 and/or VEGFR-2 in dermal fibroblasts. Based on the evidence suggesting that VEGF promotes scar formation as well as preliminary data suggesting that VEGF receptors are present on dermal fibroblasts and that these cells can respond to VEGF, the central hypothesis of the proposed studies is that VEGF promotes scar tissue deposition through direct stimulation of dermal fibroblasts. The following specific aims will be carried out to test this hypothesis: Aim 1 – Assess the effects of VEGF on fibroblast function in vitro; Aim 2 – Determine the effects of VEGF on fibroblast function in vivo. Despite the mounting evidence that VEGF regulates scar formation, no detailed mechanistic studies have been performed. Here, novel mouse models will be used to address this gap in knowledge by characterizing direct effects of VEGF on fibroblasts and dissecting the mechanisms by which VEGF promotes scar formation. The mechanisms identified as a result of these studies could extend beyond wound-induced scar formation, and have the potential to also play a role in the regulation of fibrosis in the skin as well as other organs.