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.

摘要 由胶原蛋白I的沉积定义的纤维化是发生在许多人中的破坏性病理事件， 包括心脏、肾脏、肝脏和肺在内的器官对损伤和炎症作出反应。这种纤维化反应 抑制炎症恢复，甚至可能导致器官衰竭。尽管有潜在的重要性， 已知中枢神经系统（CNS）中是否存在纤维化反应， 在诸如多发性硬化、视神经肌萎缩、中风和CNS的疾病中发生的神经炎症 感染，以及这种反应如何影响修复和恢复。利用实验性自身免疫 脑脊髓炎（EAE），神经炎症的小鼠模型，我们已经确定了一个强大的胶原蛋白I- 基于纤维化瘢痕形成覆盖神经炎性病变，我们假设这种纤维化瘢痕 抑制修复细胞进入损伤的能力。在使用谱系追踪和单个 细胞测序，我们已经确定，这种纤维化疤痕是由激活和增殖的 成纤维细胞我们已经进一步产生了分离和培养CNS成纤维细胞的方法，提供了一种体外细胞培养方法。 模型来研究这些细胞的增殖、迁移和胶原1的产生。在本提案中，我们的目标是 以确定纤维化瘢痕对神经炎症后的恢复是有益的还是有害的， 进一步研究调节纤维化瘢痕形成的机制。我们将首先确定是否抑制 纤维化瘢痕形成可导致EAE的恢复增加。然后，我们将研究TGFβ和 PDGFR信号通路调节纤维化瘢痕形成。我们假设TGFβ信号驱动了 增殖和胶原蛋白I的生产和PDGFR信号调节的迁移成纤维细胞 将纤维母细胞转移到病变处。我们的目标是确定调节纤维化瘢痕是否是一种潜在的 治疗靶点，以帮助神经炎性疾病患者康复。