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Understanding the role of VEGF in scar formation

了解 VEGF 在疤痕形成中的作用

基本信息

批准号：
10437009
负责人：
TRACI A WILGUS
金额：
$ 20.58万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10437009
关键词：
Address Affect Angiogenic Factor Apoptosis Area Behavior Blood Vessels Cells Cicatrix Clinical Collagen Complication Data Defect Deposition Dermal Embryo Endothelial Cells Esthetics Fibroblasts Fibrosis Generations Health Care Costs In Vitro Injury KDR gene Knockout Mice Knowledge Link Mediator of activation protein Mitogens Mus Myofibroblast Nutrient Operative Surgical Procedures Organ Oxygen Patients Play Process Production Regulation Role Signal Transduction Site Skin Skin wound healing Surgical incisions Testing Time Tissues VEGFA gene Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factors Wound models angiogenesis base cell type combat conditional knockout healing high reward high risk in vivo interest migration mouse model novel novel therapeutics prevent psychosocial receptor repaired skin wound tool wound wound healing

项目摘要

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.

项目概要：伤口修复过程中的并发症，包括形成过多或异常的疤痕的形成，影响数百万患者并导致巨额医疗费用。疤痕组织妨碍正常皮肤功能，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受伤或手术后形成的这种疾病将是一项重大的临床进步，将有对患者影响巨大。为了开发对抗疤痕的新疗法，需要更精确的方法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内皮生长因子-A (VEGF) 促进疤痕形成。然而，几乎没有采取任何措施来剖析 VEGF 导致疤痕形成的机制。我们的初步数据表明，成纤维细胞，细胞类型负责疤痕形成，表达 VEGF 受体，并且培养的成纤维细胞直接对 VEGF 做出反应。因此，VEGF除了调节伤口血管生成外，还可能直接刺激通过真皮成纤维细胞中的 VEGFR-1 和/或 VEGFR-2 信号传导形成疤痕。基于 VEGF 促进疤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 做出反应，该研究的中心假设是 VEGF 通过直接促进疤痕组织沉积刺激真皮成纤维细胞。将执行以下具体目标来检验这一假设：目标 1 – 体外评估VEGF对成纤维细胞功能的影响；目标 2 – 确定 VEGF 对成纤维细胞的影响在体内发挥作用。尽管越来越多的证据表明 VEGF 调节疤痕形成，但尚无详细的机制研究已执行。在这里，新型小鼠模型将用于通过表征来解决这一知识差距 VEGF 对成纤维细胞的直接影响并剖析 VEGF 促进疤痕形成的机制。这些研究结果确定的机制可能超越伤口引起的疤痕形成，并且有可能在调节皮肤和其他器官的纤维化中发挥作用。