How does the fibrotic scar regulate repair following neuroinflammation?

项目摘要 多发性硬化症（MS）是一种中枢神经系统的神经炎性疾病，其中身体的免疫功能受损。 系统攻击包围和隔离神经元轴突的髓鞘。在许多情况下， 不能被少突胶质细胞系细胞修复，导致长期残疾。关于为什么髓磷脂 是有一个物理屏障阻止少突胶质细胞谱系细胞与 轴突和修复受损的髓鞘。脊髓损伤后，创伤部位周围会形成疤痕 封闭受伤和发炎的组织瘢痕由反应性胶质细胞组成的外部胶质瘢痕组成， 星形胶质细胞和由细胞外基质蛋白组成的内部纤维化瘢痕。神经胶质瘢痕已经被研究过了 广泛作为中枢神经系统创伤的潜在治疗靶点，但对其起源和作用知之甚少 纤维化疤痕在MS中，神经胶质瘢痕也已被表征，并且报道了人体组织中的纤维化，但是 纤维化疤痕的作用还没有被研究。为了检测神经炎性病变中纤维化瘢痕的存在， 病变，小鼠诱导实验性自身免疫性脑脊髓炎（EAE），这导致 形成神经炎性脱髓鞘病变，并用作MS的小鼠模型。 疤痕存在于病变组织中，在症状发作后持续数月， 表达胶原的成纤维细胞增殖。目前还不清楚这种纤维化疤痕在 神经炎性损伤形成后的修复和激活瘢痕形成的信号。这个目标 该项目旨在确定纤维化瘢痕在神经炎性损伤形成后修复中的作用， 提示其形成的分子机制，希望能找到潜在的治疗方法， 体内的疤痕待检验的假设是，EAE诱导后形成的纤维化瘢痕阻止了 在纤维化细胞中通过TGF β途径活化进行修复和形成。一、瘢痕在EAE体内修复中的作用 通过消融分裂的纤维化细胞来防止纤维化瘢痕形成 EAE诱导后。为了确定TGF β通路的激活是否是瘢痕形成所必需的， 特异性Cre小鼠系将用于在之前有条件地敲除关键信号转导TGF β途径基因 形成疤痕此外，为了研究TGF β信号如何调节增殖，胶原蛋白的产生， 和CNS成纤维细胞的迁移，重组TGF β和途径抑制剂将被添加到一个主要的，在体外 细胞模型

Project Summary Multiple sclerosis (MS) is a neuroinflammatory disease of the central nervous system in which the body’s immune system attacks the myelin sheath that surrounds and insulates the axons of neurons. In many cases this myelin is not repaired by oligodendrocyte lineage cells leading to long term disability. One hypothesis as to why myelin is not repaired is that there is a physical barrier preventing oligodendrocyte lineage cells from interacting with axons and repairing the damaged myelin. Following spinal cord injury, a scar forms around the site of trauma and seals off the injured and inflamed tissue. The scar consists of an outer glial scar made up of reactive astrocytes and an inner fibrotic scar made of extracellular matrix proteins. The glial scar has been studied extensively as a potential therapeutic target for CNS trauma, but much less is known about the origins and role of the fibrotic scar. In MS, the glial scar has also been characterized, and fibrosis in human tissue reported, but the role of a fibrotic scar has not been investigated. To test for the presence of a fibrotic scar in neuroinflammatory lesions, mice were induced with experimental autoimmune encephalomyelitis (EAE), which leads to the formation of neuroinflammatory demyelinated lesions and is used as a mouse model of MS. An extensive fibrotic scar was present in the lesioned tissue that remained for months following symptom onset and arose from the proliferation of collagen-expressing fibroblasts. Nothing is known about the role this fibrotic scar plays in repair following neuroinflammatory lesion formation and the signals that activate scar formation. The goal of this project is to define the role of the fibrotic scar in repair following neuroinflammatory lesion formation and the molecular mechanisms that cue its formation, with the hopes of identifying potential therapeutics to manipulate the scar in vivo. The hypothesis to be tested is that the fibrotic scar that forms following EAE induction prevents repair and forms through TGFβ pathway activation in fibrotic cells. First, the role of the scar in EAE repair in vivo will be determined by preventing the fibrotic scar from forming through the ablation of dividing fibrotic cells following EAE induction. To determine if TGFβ pathway activation is necessary for scar formation, a fibroblast- specific Cre mouse line will be used to conditionally knockout key signaling TGFβ pathway genes prior to scar formation. Additionally, to study how TGFβ signaling regulates the proliferation, collagen production and migration of CNS fibroblasts, recombinant TGFβ and pathway inhibitors will be added to a primary, in vitro cell model.