How do CNS fibroblasts regulate the response to neuroinflammation?

中枢神经系统成纤维细胞如何调节对神经炎症的反应？

• 批准号: 10841263
• 负责人: Richard Daneman
• 金额: $ 4.02万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10841263
• 关键词: Affect; Cells; Central Nervous System; Central Nervous System Diseases; Central Nervous System Infections; Cicatrix; Collagen; Deposition; Disease; Event; Experimental Autoimmune Encephalomyelitis; Fibroblasts; Fibrosis; Goals; Heart; Inflammation; Inflammatory; Kidney; Lead; Lesion; Liver; Lung; Methods; Molecular; Multiple Sclerosis; Neuromyelitis Optica; Organ; Organ failure; PDGFRB gene; Pathologic; Patients; Physiological; Production; Proliferating; Recovery; Signal Pathway; Signal Transduction; Stroke; Testing; Therapeutic; Tissues; Transforming Growth Factor beta; in vitro Model; migration; mouse model; neuroinflammation; repaired; reparative capacity; response; response to injury; single cell sequencing; therapeutic target

ABSTRACT Fibrosis, defined by the deposition of collagen I, is a devastating pathological event that occurs in many organs including the heart, kidney, liver and lung in response to injury and inflammation. This fibrotic response inhibits recovery inflammation and can even lead to organ failure. Despite the potential importance, very little is known about whether there is a fibrotic response in the central nervous system (CNS) following neuroinflammation that occurs in diseases such as multiple sclerosis, neuromyelitis optica, stroke and CNS infections, and how this response affects repair and recovery. Using experimental autoimmune encephalomyelitis (EAE), a mouse model of neuroinflammation, we have identified that a robust collagen I- based fibrotic scar forms covering the neuroinflammatory lesion and we hypothesize that this fibrotic scar inhibits the ability of reparative cells to enter the lesion. In preliminary studies using lineage tracing and single cell sequencing, we have identified that this fibrotic scar is formed by the activation and proliferation of fibroblasts. We have further generated methods to isolate and culture CNS fibroblasts providing an in vitro model to study the proliferation, migration and collagen 1 production from these cells. In this proposal we aim to determine whether the fibrotic scar is helpful or harmful for recovery following neuroinflammation and to further study the mechanisms that regulate fibrotic scar formation. We will first determine whether inhibition of fibrotic scar formation can lead to an increased recovery from EAE. We will then examine whether TGFβ and PDGFR signaling pathways regulate fibrotic scar formation. We hypothesize that TGFβ signaling drives the proliferation and collagen I production by the fibroblasts and that PDGFR signaling regulates the migration of the fibroblasts to the lesion. Our goal is to determine whether modulating the fibrotic scar is a potential therapeutic target to aid in recovery for patients with neuroinflammatory diseases.

抽象的 由胶原蛋白I的沉积定义的纤维化是一个毁灭性的病理事件，发生在许多人中 响应损伤和炎症的器官，包括心脏，肾脏，肝脏和肺部。这种纤维化反应 抑制恢复感染，甚至会导致器官衰竭。尽管潜在的重要性，但很少 知道中枢神经系统（CNS）是否有纤维化反应 神经炎症发生在多发性硬化症，神经肌炎Optica，中风和CN等疾病中 感染以及这种反应如何影响修复和恢复。使用实验自身免疫 脑脊髓炎（EAE）是一种神经炎症的小鼠模型，我们已经确定了坚固的胶原蛋白I- 基于纤维化的疤痕形式涵盖神经炎症病变，我们假设这种纤维化疤痕 在使用谱系跟踪和单一的初步研究中 细胞测序，我们已经确定这种纤维化疤痕是由激活和增殖形成的 成纤维细胞。我们有进一步生成的方法来分离和培养CNS成纤维细胞，可提供体外 模型以研究这些细胞的增殖，迁移和胶原蛋白1产生。在这个建议中，我们的目标 确定纤维化疤痕对神经炎症后的恢复是否有帮助或有害 进一步研究调节纤维化疤痕形成的机制。我们将首先确定是否抑制 纤维化疤痕形成会导致EAE的恢复增加。然后，我们将检查TGFβ和 PDGFR信号通路调节纤维化疤痕形成。我们假设TGFβ信号驱动 成纤维细胞产生增殖和胶原蛋白I，PDGFR信号传导调节迁移 成纤维细胞可为病变。我们的目标是确定调节纤维化疤痕是否潜在 治疗靶标有助于神经炎症性疾病患者的康复。