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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：
9925652
负责人：
Cayce Elizabeth Dorrier
金额：
$ 3.84万
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/9925652
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 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 conditional knockout 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.

项目总结