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

皮肤中新型促纤维化调节途径的评估

• 批准号: 9234862
• 负责人: TRACI A WILGUS
• 金额: $ 20.42万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9234862
• 关键词: Adipocytes; Adult; Agonist; Architecture; Binding; Cells; Cicatrix; Collagen; Cosmetics; Cutaneous; Data; Dermal; Development; Embryo; Embryonic Development; Evaluation; Fibroblasts; Future; Glycoproteins; Goals; Growth; Hepatocyte; Impairment; Injury; Knockout Mice; Ligands; Mediating; Minor; Modeling; Mus; Natural regeneration; Normal tissue morphology; Organ; Pathway interactions; Patients; Play; Process; Production; Property; Proteins; Proteomics; Psychological Impact; Psychosocial Influences; Quality of life; Regulatory Pathway; Role; Serum; Skin; Skin wound; TLR4 gene; Testing; Tissues; Work; Wound Healing; alpha-Fetoproteins; base; cell type; differential expression; early embryonic stage; fetal; healing; in utero; in vivo; injured; joint mobilization; keratinocyte; migration; mouse model; new therapeutic target; novel; novel therapeutics; prevent; regenerative; repaired; response; restoration; therapy design

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.

项目摘要： 对组织损伤的理想反应是再生，正常组织的完全恢复 建筑学。不幸的是，成熟的皮肤通常通过修复过程愈合，从而导致形成 疤痕组织而不是正常组织。除了与疤痕相关的化妆品问题外，疤痕组织 比正常皮肤弱，在功能上有缺陷。有趣的是，在胚胎的早期阶段 发育，胎儿皮肤能够在没有疤痕的情况下愈合。我们使用胎儿伤口愈合的鼠标模型 比较在胚胎第15天（E15）和纤维化，疤痕形成时产生的再生，无疤痕 在胚胎第18天（E18）产生的伤口。我们的实验室最近完成了初步研究 证明糖蛋白fetuin-a（Feta）的存在于E18成纤维细胞中的水平明显更高， E18皮肤和E18伤口与E15的伤口相比。初步数据还表明介绍 胎儿进入E15胎儿伤口会破坏无疤痕的愈合过程。这里提出的研究将测试 羊膜刺激成纤维细胞并促进疤痕形成的能力。因为已显示羊膜与 并激活脂肪细胞和其他TLR4激动剂中的TLR4可以刺激成纤维细胞，我们将 还可以探索TLR4激活作为一种潜在的机制，该机制刺激成纤维细胞激活和疤痕 组织生产。 拟议研究的中心假设是，羊乳酪通过 成纤维细胞以TLR4依赖性方式。提出了以下具体目的来检验假设：目的 1 - 检查羊乳酪对培养的皮肤成纤维细胞的影响；目标2 - 确定羊乳酪是否促进疤痕 体内形成。 该应用程序基于我们的实验室生成的新数据，表明羊乳酪与疤痕有关 形成。关于羊膜在皮肤中的功能以及羊乳酪对成纤维细胞/疤痕的影响知之甚少 尚未检查编队。因此，这项工作很重要，因为它将提供重要的新 科学信息。这些研究有可能通过建立Feta介导的TLR4来影响该领域 激活作为一种新的机械途径，涉及功能失调，使人衰弱的疤痕的形成。