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

纤维化是一种异常的伤口愈合反应，细胞增殖并分泌胶原形成疤痕。 并破坏器官功能。这在许多慢性疾病中都会发生，包括肝硬变和 动脉粥样硬化，以及自身免疫性疾病，如硬皮病，皮肤和其他器官纤维化是 主要特征。目前，大多数类型的纤维化都没有有效的治疗方法。尽管 纤维化在许多疾病中的流行，在细胞和组织水平上的驱动机制很大程度上是 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，我们已经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，我们将使用诱导PDGFR的小鼠的皮肤损伤试验 识别由PDGFR途径激活改变的特定伤口修复过程的信号。我们会 在周细胞中特异性地激活PDGFR信号，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着关键作用。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 假设皮肤中的Nestin+周细胞是间充质干细胞(MSCs)，PDGF途径 活性改变了它们的分化，走向肌成纤维细胞的命运。在特定目标3中，我们将分离Nestin+ 并确定哪些MSC过程受使用干细胞的PDGF信号调节 化验。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鉴定基因 受PDGFR途径调控的程序。最后，我们将测试Nestin+MSCs的纤维化潜能 移植试验。总之，这些实验将探索鲜为人知的肝纤维化机制。 并确定受主要促纤维化生长调控的细胞和分子机制 因素。对纤维化机制的了解有望导致合理的治疗 限制或逆转疾病的方法。

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.