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: 10456525
• 负责人: Richard Daneman
• 金额: $ 15.8万
• 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/10456525
• 关键词: Affect; Cells; 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; Neuraxis; Neuromyelitis Optica; Organ; Organ failure; PDGFRB gene; Pathologic; Patients; Physiological; Production; Recovery; Signal Pathway; Signal Transduction; Stroke; Testing; Therapeutic; Tissues; Transforming Growth Factor beta; base; 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 纤维化是由 I 型胶原沉积定义的，是一种破坏性的病理事件，发生在许多疾病中。 包括心脏、肾脏、肝脏和肺在内的器官对损伤和炎症的反应。 抑制恢复性炎症，甚至可能导致器官衰竭，尽管具有潜在的重要性，但效果却微乎其微。 了解中枢神经系统 (CNS) 是否存在纤维化反应 多发性硬化症、视神经脊髓炎、中风和中枢神经系统等疾病中发生的神经炎症 感染，以及这种反应如何影响实验性自身免疫的修复和恢复。 脑脊髓炎 (EAE) 是一种神经炎症小鼠模型，我们发现一种强大的 I 型胶原蛋白- 基于纤维化疤痕形式覆盖神经炎症病变，我们追求这种纤维化疤痕 在使用谱系追踪和单一的初步研究中，抑制修复细胞进入病变的能力。 细胞测序，我们发现这种纤维化疤痕是由细胞活化和增殖形成的 我们进一步开发了分离和培养中枢神经系统成纤维细胞的方法，提供了体外实验。 我们的目标是研究这些细胞的增殖、迁移和胶原蛋白 1 生成的模型。 确定纤维化疤痕对神经炎症后的恢复是否有益或有害 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。 纤维化疤痕的形成可以促进 EAE 的恢复，然后我们将检查 TGFβ 和 PDGFR 信号通路调节纤维化疤痕形成。 成纤维细胞的增殖和 I 型胶原蛋白的产生，PDGFR 信号调节 I 型胶原蛋白的迁移 我们的目标是确定调节纤维化疤痕是否具有潜力。 帮助神经炎症性疾病患者康复的治疗目标。