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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要：对组织损伤的理想反应是再生，正常组织完全恢复不幸的是，成熟的皮肤通常通过修复过程来愈合，从而形成。疤痕组织代替正常组织除了与疤痕相关的美容问题外，疤痕组织。比正常皮肤脆弱并且有功能缺陷。发育过程中，胎儿皮肤能够愈合且不留疤痕。我们使用胎儿伤口愈合的小鼠模型来进行研究。比较胚胎第 15 天 (E15) 产生的再生、无疤痕伤口和纤维化、疤痕形成伤口我们的实验室最近完成了胚胎第 18 天（E18）产生的伤口。证明糖蛋白胎球蛋白-A (FetA) 在 E18 成纤维细胞中的含量明显较高， E18的皮肤，以及E18的伤口与E15的手臂相比，初步数据也表明了这一点。 FetA 进入 E15 胎儿伤口会破坏无疤痕愈合过程。这里提出的研究将测试 FetA 刺激成纤维细胞并促进疤痕形成的能力，因为 FetA 已被证明可以结合。并激活脂肪细胞中的 TLR4，其他 TLR4 激动剂已被证明可以刺激成纤维细胞，我们将还探索了 TLR4 激活作为 FetA 刺激成纤维细胞激活和疤痕的潜在机制组织生产。拟议研究的中心假设是 FetA 通过以下方式刺激疤痕组织的产生：提出以下具体目标来检验该假设： 1 – 检查 FetA 对培养的真皮成纤维细胞的影响；目标 2 – 确定 FetA 是否促进疤痕形成体内形成。该应用程序基于我们实验室生成的新数据，表明 FetA 与疤痕有关关于 FetA 在皮肤中的功能以及 FetA 对成纤维细胞/疤痕的影响知之甚少。因此，这项工作意义重大，因为它将提供重要的新内容。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制途径参与功能失调、使人衰弱的疤痕的形成。