How does the fibrotic scar regulate repair following neuroinflammation?

纤维化疤痕如何调节神经炎症后的修复？

基本信息

批准号：
9759713
负责人：
Cayce Elizabeth Dorrier
金额：
$ 3.79万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9759713
关键词：
Ablation Affect American Area Astrocytes Axon Blood Vessels Brain Injuries Cell Lineage Cell Proliferation Cell model Cells Central Nervous System Diseases Chronic Cicatrix Collagen Cues Disease Disease Progression Experimental Autoimmune Encephalomyelitis Extracellular Matrix Proteins Fibroblasts Fibrosis Ganciclovir Genes Goals Growth Histologic Human Immune Immune system In Vitro Infiltration Injury Knock-out Lead Learning Lesion Molecular Motor Multiple Sclerosis Multiple Sclerosis Lesions Mus Myelin Myelin Sheath Neuraxis Neurons Onset of illness Outcome Pathway interactions Patients Peripheral Pharmaceutical Preparations Play Process Production Proliferating Recombinants Recovery Reporting Role Signal Transduction Simplexvirus Site Smad Proteins Spinal Cord Spinal cord injury Symptoms Testing Therapeutic Thymidine Kinase Time Tissues Transforming Growth Factor beta Trauma Traumatic CNS injury Up-Regulation brain tissue disability human tissue in vitro Model in vivo inhibitor/antagonist injured insight migration mouse model myelination neuroinflammation novel therapeutics oligodendrocyte lineage prevent remyelination repaired seal single cell sequencing therapeutic target tissue regeneration tissue repair transcriptome sequencing

项目摘要

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.

项目摘要多发性硬化症（MS）是中枢神经系统的神经炎症性疾病，人体免疫系统攻击周围环境并绝缘神经元轴突的髓鞘。在许多情况下，这个髓磷脂未通过导致长期残疾的少突胶质细胞谱系细胞修复。一个假设是为什么髓鞘没有修复的是，存在一个物理屏障，可防止少突胶质细胞谱系细胞与轴突并修复受损的髓鞘。脊髓损伤后，创伤部位周围形成疤痕并密封受伤和发炎的组织。疤痕由由反应性组成的外神经胶质疤痕组成星形胶质细胞和由细胞外基质蛋白制成的内部纤维化疤痕。神经胶质疤痕已研究广泛地是中枢神经系统创伤的潜在治疗靶标，但对起源和作用的了解少得多纤维化疤痕。在MS中，神经胶质疤痕也被表征，人类组织中的纤维化报告，但尚未研究纤维化疤痕的作用。测试神经炎症中纤维化疤痕的存在病变，用实验性自身免疫性脑脊髓炎（EAE）诱导小鼠，这导致了神经炎性脱髓鞘病变的形成，用作MS的小鼠模型。广泛的纤维化疤痕存在于病变的组织中，症状发作后几个月保留了几个月表达胶原蛋白的成纤维细胞的增殖。这种纤维化疤痕在中扮演的角色一无所知神经炎性病变形成和激活疤痕形成的信号后修复。目标的目标项目是在神经炎性病变形成和提示其形成的分子机制，希望识别潜在的治疗剂来操纵体内疤痕。要测试的假设是，EAE诱导后形成的纤维化疤痕阻止通过纤维化细胞中的TGFβ途径激活修复和形成。首先，疤痕在体内的EAE修复中的作用通过防止纤维化疤痕通过分裂的纤维化细胞的消融来确定在EAE诱导之后。为了确定TGFβ途径激活是否需要疤痕形成，成纤维细胞 - 特定的CRE小鼠系将用于有条件地敲除钥匙信号TGFβ途径基因疤痕形成。此外，要研究TGFβ信号如何调节增殖，胶原蛋白的产生 CNS成纤维细胞，重组TGFβ和途径抑制剂的迁移将添加到主要的体外细胞模型。