PDGF-regulated cell fate and dermal fibrosis

PDGF调节的细胞命运和真皮纤维化

• 批准号: 10016998
• 负责人: LORIN E OLSON
• 金额: $ 38.39万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10016998
• 关键词: Address; Adipocytes; Adipose tissue; Binding; Biological Models; Blood Vessels; Cell Differentiation process; Cell Proliferation; Cell model; Cells; Cerebellum; Cessation of life; Cicatrix; Clinical; Collagen; Complex; DNA Binding; Dermal; Dermis; Development; Disease; Epithelial; Epithelium; Equilibrium; Excision; Extracellular Matrix; FRAP1 gene; Fibroblasts; Fibrosis; Genes; Genetic; Genetic Models; Genetic Transcription; Goals; Granulation Tissue; Growth Factor; In Vitro; Inflammatory; Knowledge; Laboratories; Lipids; Literature; Maps; Mediating; Mesenchymal; Mesenchymal Stem Cells; Molecular; Mus; Natural regeneration; Neurons; Normal tissue morphology; Nuclear Protein; Organ; Pathway interactions; Pharmacology; Phosphatidylinositols; Phosphotransferases; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor alpha Receptor; Prevention strategy; Process; Research; Role; Signal Pathway; Signal Transduction; Skin; Structure; Suggestion; Testing; Tissues; Transplantation; Work; adipocyte differentiation; base; cell motility; gain of function mutation; genetic approach; graft vs host disease; healing; improved; in vivo; injured; innovation; lipid biosynthesis; loss of function mutation; mTOR Signaling Pathway; migration; molecular targeted therapies; mutant; neuroregulation; novel strategies; novel therapeutic intervention; overexpression; receptor; response; response to injury; restoration; skin wound; stem cells; transcription factor; treatment strategy; wound bed; wound healing

Fibrosis occurs when overactive mesenchymal cells generate excess collagen that replaces functional tissue. The skin is a major target of fibrosis resulting from aberrant wound healing, graft-versus-host disease, and au- toimmunity. In some organs, fibrosis is accompanied by the disappearance of lipid-storing cells and replace- ment with pro-fibrotic cells, which suggests a dysregulation of fibroblast-adipocyte cell fate. There is a need for better understanding of the mechanisms of fibrosis because we lack treatment strategies that specifically target the fibrogenic process in most diseases. Elevated platelet-derived growth factor (PDGF) signaling is one of the major drivers of fibroproliferative disorders. There are two receptors, PDGF receptor-α (PDGFRα) and β (PDGFRβ), which have much in common but they are regulated differently and have distinct cellular effects that have not been addressed in the fibrosis literature. Results from the applicant's laboratory point to PDGFRα as the major regulator of fibrosis in mice compared to PDGFRβ. More specifically, in dermis-derived progenitor cells, PDGFRα activation blocks adipogenesis and induces the cells to differentiate into pro-fibrotic cells. How- ever, the signaling and transcriptional mechanisms underlying this cell fate switch are unknown. It also remains to be tested whether removal of PDGFRα can improve the tissue response to injury, resulting in less fibrosis and increased regeneration of adipocytes. The hypothesis underlying this project is that PDGFRα regulates the balance of fibrosis versus adipogenesis through the PI3K/Akt/mTOR signaling pathway and a new PDGFRα- regulated transcription factor. Aim 1 will use dermis-derived mesenchymal progenitor cells (MPCs) as a model system to investigate whether PDGFRα-regulated PI3K/Akt/mTOR signaling is required and sufficient for the cell-fate switch. Aim 2 will explore the role of a new PDGFRα-regulated transcription factor in fibro-adipogenic fate, using MPCs and mice as model systems, and determine how PDGFRα regulates this new factor in MPCs. Aim 3 will study dermal wound healing in mice with gain- and loss-of-function mutations in PDGFRα to identify the processes by which PDGFRα regulates scar formation. Mutant cells will be fate mapped to determine how different levels of PDGFRα activity regulate fibro-adipogenic fate in vivo. This work is expected to reveal how the PDGFRα signaling pathway mediates its pro-fibrotic/anti-adipogenic effects on dermal progenitor cells. The discovery of signaling pathways that induce mesenchymal cells towards a profibrotic fate will inform the devel- opment of new therapeutic approaches. Knowledge of how DNA-binding factors regulate MPC fate will have major impact on the understanding of core fibrosis mechanisms. And identifying the specific role of PDGFRα in scar formation will begin to establish it as a molecular target for therapy. The resulting generalizable knowledge about how fibro-adipogenic fate is controlled will improve the restoration of structure and function to damaged organs.

当过度活跃的间充质细胞产生过量的胶原蛋白取代功能组织时，就会发生纤维化。 皮肤是由异常伤口愈合、移植物抗宿主病和Au诱导的纤维化的主要靶点。 免疫力。在某些器官中，纤维化伴随着贮脂细胞的消失和替代， 这表明成纤维细胞-脂肪细胞命运的失调。有必要 更好地了解纤维化的机制，因为我们缺乏专门针对 大多数疾病的纤维化过程。血小板衍生生长因子（PDGF）信号传导升高是导致血小板减少的原因之一。 纤维增生性疾病的主要驱动因素。有两种受体，PDGF受体-α（PDGFRα）和β （PDGFRβ），它们有很多共同之处，但它们的调节方式不同，并具有不同的细胞效应 在纤维化文献中还没有提到。申请人实验室结果指向PDGFRα 作为小鼠纤维化的主要调节因子。更具体地，在真皮衍生的祖细胞中， 细胞，PDGFRα激活阻断脂肪生成并诱导细胞分化为促纤维化细胞。怎么-- 然而，这种细胞命运转换背后的信号和转录机制尚不清楚。委员会还 待检测去除PDGFRα是否可以改善组织对损伤的反应，从而减少纤维化 并增加脂肪细胞的再生。该项目的基本假设是PDGFRα调节 通过PI 3 K/Akt/mTOR信号通路和新的PDGFRα- 调节转录因子目的1将真皮来源的间充质祖细胞作为模型 研究PDGFRα调节的PI 3 K/Akt/mTOR信号传导是否是PDGFRα调节的PI 3 K/Akt/mTOR信号传导所必需的和足够的系统。 细胞命运转换目的2探讨PDGFRα调控的转录因子在成纤维细胞脂肪形成中的作用 命运，使用MPC和小鼠作为模型系统，并确定PDGFRα如何调节MPC中的这种新因子。 目的3将研究PDGFRα获得性和丧失性功能突变小鼠的皮肤伤口愈合，以确定 PDGFRα调节瘢痕形成的过程。突变细胞将被命运映射，以确定如何 不同水平的PDGFRα活性调节体内纤维脂肪形成的命运。这项工作有望揭示 PDGFRα信号通路介导其对真皮祖细胞的促纤维化/抗脂肪形成作用。的 诱导间充质细胞走向促纤维化命运的信号通路的发现将告知发展， 新的治疗方法的发展。了解DNA结合因子如何调节MPC的命运， 对核心纤维化机制的理解产生重大影响。并确定PDGFRα的具体作用， 瘢痕形成将开始使其成为治疗的分子靶点。由此产生的可推广的 关于纤维脂肪形成命运如何控制的知识将改善结构和功能的恢复， 受损器官