Understanding connective tissue development and disease with PDGFR-driven.....

通过 PDGFR 驱动了解结缔组织发育和疾病......

• 批准号: 9234553
• 负责人: Lorin Olson
• 金额: $ 33.29万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9234553
• 关键词: Adipocytes; Adipose tissue; Atherosclerosis; Attention; Autoimmune Diseases; Autoimmunity; Automobile Driving; Bioinformatics; Biological Assay; Bone Marrow; Bone Marrow Stem Cell; Cardiovascular Diseases; Cell Differentiation process; Cell Separation; Cell physiology; Cells; Chronic; Chronic Disease; Cicatrix; Cirrhosis; Collagen; Colony-Forming Units Assay; Data; Developmental Biology; Disease; Equilibrium; Extracellular Matrix; FDA approved; Fibroblasts; Fibrosis; Functional disorder; Genes; Growth Factor; Inflammation; Inflammatory; Knowledge; Label; Lead; Liver Cirrhosis; Liver diseases; Mesenchymal Stem Cells; Molecular; Mus; Myofibroblast; Nude Mice; Oklahoma; Organ; Paracrine Communication; Pathway interactions; Patient-Focused Outcomes; Pericytes; Pharmaceutical Preparations; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor Receptor; Platelet-Derived Growth Factor alpha Receptor; Population; Prevalence; Process; Proliferating; Receptor Signaling; Reporter; Research; Role; Scleroderma; Signal Transduction; Signaling Molecule; Skin; Skin injury; Skin wound; Source; Stromal Cells; Testing; Therapeutic; Tissues; Transforming Growth Factor beta; Transgenes; Transplantation; Trees; Wild Type Mouse; Work; Wound Healing; body system; cell type; connective tissue development; cytokine; effective therapy; experimental study; healing; immunoregulation; in vitro Assay; mouse model; nestin protein; novel; programs; response; treatment strategy; wound

Fibrosis is an aberrant wound-healing response where cells proliferate and secrete collagen that forms scar tissue and disrupts organ functions. This occurs in many chronic diseases including liver cirrhosis and atherosclerosis, as well as autoimmune diseases like scleroderma where skin and other organ fibrosis is the principal feature. There are currently no effective treatments for most types of fibrosis. Despite the prevalence of fibrosis in many diseases, the driving mechanisms at the cell and tissue level are largely unknown. Our research is focused on the ability of platelet-derived growth factor receptor (PDGFR) signaling to cause fibrosis in the skin, and we have devised new mouse models to identify the underlying cellular and molecular mechanisms. In Specific Aim 1, we will use skin-injury assays in mice with induced PDGFR signaling to identify specific wound-repair processes that are altered by PDGFR pathway activation. We will activate PDGFR signaling specifically in pericytes because our preliminary data indicate that this cell type has a key role in fibrosis following skin injury. In Specific Aim 2 we will use fate mapping to determine the lineage contribution of pericytes to the myofibroblast population that is directly responsible for fibrosis. We hypothesize that nestin+ pericytes in the skin are mesenchymal stem cells (MSCs) and that PDGF pathway activity alters their differentiation towards a myofibroblast fate. In Specific Aim 3 we will isolate nestin+ MSCs from the skin and determine which MSC processes are regulated by PDGF signaling using stem cell assays. We will also use microarrays and bioinformatics to characterize this cell type and identify the gene programs regulated by the PDGFR pathway. Finally, we will test the fibrotic potential of nestin+ MSCs using transplantation assays. Together, these experiments will explore poorly understood fibrotic mechanisms in the skin and identify cellular and molecular mechanisms that are regulated by a major pro-fibrotic growth factor. An understanding of the mechanisms of fibrosis can be expected to lead to rational therapeutic approaches to limit or reverse disease.

纤维化是一种异常的伤口愈合反应，其中细胞增殖并分泌形成瘢痕的胶原蛋白 组织和破坏器官功能。这发生在许多慢性疾病中，包括肝硬化和 动脉粥样硬化，以及自身免疫性疾病，如硬皮病，其中皮肤和其他器官纤维化是 主要特征。目前对大多数类型的纤维化没有有效的治疗方法。尽管 尽管纤维化在许多疾病中普遍存在，但细胞和组织水平的驱动机制在很大程度上 未知我们的研究集中在血小板衍生生长因子受体（PDGFR）信号转导的能力， 导致皮肤纤维化，我们设计了新的小鼠模型来识别潜在的细胞和 分子机制在具体目标1中，我们将在诱导PDGFR的小鼠中使用皮肤损伤试验 信号传导以识别因PDGFR途径激活而改变的特定伤口修复过程。我们将 激活PDGFR信号，特别是在周细胞，因为我们的初步数据表明，这种细胞类型， 在皮肤损伤后的纤维化中起关键作用。在具体目标2中，我们将使用命运映射来确定 周细胞对肌成纤维细胞群体的谱系贡献直接导致纤维化。我们 假设皮肤中巢蛋白+周细胞是间充质干细胞（MSC），并且PDGF途径 活性改变它们向肌成纤维细胞命运的分化。在特定目标3中，我们将分离巢蛋白+ 从皮肤中提取MSC，并使用干细胞确定哪些MSC过程受PDGF信号转导的调节 分析。我们还将使用微阵列和生物信息学来表征这种细胞类型并识别基因 由PDGFR途径调节的程序。最后，我们将使用免疫组织化学方法测试巢蛋白+MSC的纤维化潜力。 移植试验总之，这些实验将探索对纤维化机制知之甚少， 皮肤和鉴定由主要促纤维化生长调节的细胞和分子机制 因子对纤维化机制的理解有望导致合理的治疗方法， 限制或逆转疾病的方法。