MFAP5 and Skin Scar Formation

MFAP5 和皮肤疤痕形成

• 批准号: 10605379
• 负责人: Chen Han
• 金额: $ 5.27万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-02 至 2027-05-01
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605379
• 关键词: Adult; Affect; Apoptotic; Architecture; Area; Bioinformatics; Biological Assay; Cells; Chemoresistance; Cicatrix; Collagen; Complex; Contracture; Data; Development; Disease; Esthetics; Extracellular Matrix; Fibroblasts; Fibrosis; Gene Expression; Genes; Genomics; Goals; Hemostatic function; Human; Hypertrophic Cicatrix; Impairment; In Vitro; Inflammation; Inflammatory; Ingestion; Institution; Keloid; Knockout Mice; Lead; Link; Liver Cirrhosis; MFAP1 gene; Malignant Neoplasms; Mediator; Microfibrils; Mus; Myocardial Infarction; Myofibroblast; Ontology; Organ; Outcome; Pain; Pathogenesis; Pathologic; Pathway Analysis; Pathway interactions; Patients; Phagocytes; Phase; Phenotype; Process; Production; Prognostic Marker; Proliferating; Proteins; Pulmonary Fibrosis; RNA; Regulation; Research; Research Personnel; Research Training; Resources; Role; Signal Pathway; Signal Transduction; Skin; Skin wound healing; Source; Surface; Systemic Scleroderma; Techniques; Tissues; Training; Transfection; Up-Regulation; Width; Work; angiogenesis; body system; career development; cell motility; comparison control; design; differential expression; experimental study; extracellular; fibrillin; healing; human disease; idiopathic pulmonary fibrosis; in vivo; laboratory experiment; migration; novel; novel therapeutics; overexpression; recruit; repair function; response; single-cell RNA sequencing; skin fibrosis; skin regeneration; targeted biomarker; therapeutic biomarker; tissue injury; tissue repair; transcriptome; transcriptome sequencing; vector; wound; wound closure; wound healing

PROJECT SUMMARY This application proposes a customized research training plan designed to promote the development of the applicant into an independent investigator. The plan includes advanced training in both bioinformatics and laboratory experimentation, along with tailored professional and career development opportunities. The training plan is supported by the outstanding availability of local and institutional resources at UIC. The proposed research will examine the mechanisms that control scar formation, a common result of the healing response. In adults, the outcome of wound repair is almost always a fibrous scar composed of disorganized extracellular matrix (ECM). Although regulation of scar formation is complex, a key feature is fibroblast (FB) activation, which generates ECM and contractile forces. Scarring and fibrosis occurs in many tissues and can cause significant impairments of the organ system affected. Recent studies in our lab have identified a novel FB function in wounds that may be linked to scar formation. These studies show that wound FBs can act as non- professional phagocytes and ingest apoptotic cells. Following apoptotic cell engulfment, FBs develop a fibrotic phenotype with enhanced migration, increased contractility (α-SMA expression), and increased collagen synthesis. One factor found to be significantly upregulated in fibrotic phagocytic FBs is microfibril-associated protein 5 (MFAP5 or microfibril-associated glycoprotein 2/MAGP2). MFAP5 influences microfibril function and can regulate cell signaling pathways. Interestingly, MFAP5 has been linked to fibrosis in several human diseases, including some cancers and fibrotic diseases. Still, little is known regarding its role in wound healing and scar formation. Therefore, the goal of this study is to gain a better understanding of the function of MFAP5 in skin healing and scar formation. We hypothesize that upregulation of MFAP5 in the healing skin wound modifies the FB response and promotes scar formation. In this study, the role of MFAP5 in wound healing will be investigated in Mfap5-/- mice, a well-established Mfap5 knock out mouse line. The effect of MFAP5 on FB phenotype will be further investigated in vitro. This proposal will utilize in vivo and in vitro wound healing assays and advanced bioinformatics techniques. Aim 1 will assess how the loss of MFAP5 affects wound healing, including scar collagen content and architecture, wound breaking strength, myofibroblast activation, angiogenesis, and wound closure. Single-cell RNA sequencing will be used to identify the FB subpopulation that produces MFAP5 during wound healing. Aim 2 will examine how MFAP5 influences FB function and gene expression by utilizing in vitro wound healing assays as well as bulk RNA-sequencing and functional pathway analysis. Together, the Aims will lead to a better understanding of the importance of MFAP5 in healing skin wounds and scar formation. Information gained from the proposed research may lead to the development of novel therapeutics and/or discovery of a prognostic biomarker for treatment of fibrotic diseases.

项目摘要 该申请提出了一个定制的研究培训计划，旨在促进 申请人进入独立调查员。该计划包括对生物信息学和 实验室实验，以及量身定制的专业和职业发展机会。培训 计划在UIC的本地和机构资源的出色可用性支持计划。提议 研究将检查控制疤痕形成的机制，这是愈合反应的常见结果。在 成年人，伤口修复的结果几乎总是由纤维疤痕，由细胞外杂质组成 矩阵（ECM）。尽管疤痕形成的调节是复杂的，但关键特征是成纤维细胞（FB）激活， 产生ECM和收缩力量。疤痕和纤维化发生在许多组织中，可能导致 器官系统受到的重大损害受到影响。我们实验室的最新研究已经确定了一种新颖的FB 可能与疤痕形成有关的伤口功能。这些研究表明，赢得FB可以是非 - 专业的吞噬细胞和摄入的凋亡细胞。凋亡细胞吞噬后，FBS发展出纤维化 表型具有增强的迁移，收缩力增加（α-SMA表达）和胶原蛋白增加 合成。在纤维化吞噬FBS中发现的一个因素已显着更新是微纤维相关的 蛋白5（MFAP5或微纤维相关的糖蛋白2/MAGP2）。 MFAP5影响微纤维功能和 可以调节细胞信号通路。有趣的是，MFAP5与几个人的纤维化有关 疾病，包括一些癌症和纤维化疾病。尽管如此，关于其在伤口愈合中的作用知之甚少 和疤痕形成。因此，这项研究的目的是更好地了解MFAP5的功能 在皮肤愈合和疤痕形成中。我们假设MFAP5在愈合皮肤伤口中上调 修改FB响应并促进疤痕形成。在这项研究中，MFAP5在伤口愈合中的作用 将在MFAP5 - / - 小鼠中进行研究，这是一条公认的MFAP5敲除鼠标线。 MFAP5对 FB表型将在体外进一步研究。该建议将利用体内和体外伤口愈合 测定和先进的生物信息学技术。 AIM 1将评估MFAP5的损失如何影响伤口 康复，包括疤痕胶原蛋白含量和建筑，伤口断裂强度，肌纤维细胞激活， 血管生成和伤口闭合。单细胞RNA测序将用于识别FB亚群 在伤口愈合过程中会产生MFAP5。 AIM 2将检查MFAP5如何影响FB功能和基因 通过使用体外伤口愈合测定法以及大量RNA测序和功能途径的表达 分析。在一起，目标将使MFAP5在愈合皮肤中的重要性有更好的了解 风和疤痕形成。从拟议的研究中获得的信息可能导致 新的疗法和/或发现用于治疗纤维化疾病的预后生物标志物。