Unravelling the role of cell-specific interleukin-1B during cerebrovascular inflammation after stroke

揭示细胞特异性白细胞介素 1B 在中风后脑血管炎症中的作用

• 批准号: 2896596
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2896596
• 关键词: Unravelling; role; cell; specific; interleukin

Interleukin-1 (IL-1) drives inflammation after stroke, contributing to brain damage and poorer outcome. Blocking IL-1 actions with the IL-1 receptor antagonist (IL-1Ra) is beneficial in pre-clinical stroke models, and studies in stroke patients show that IL-1Ra is safe and may improve clinical outcomes. Importantly, IL-1 is expressed as two isoforms, IL-1 alpha (IL-1a) and IL-1 beta (IL-1B), but the specific function of each ligand in stroke is completely unknown. We have recently generated new conditional IL-1 genetic mouse models to precisely identify the relative contribution of IL-1a and IL-1B during stroke. This can be achieved by selectively deleting each of those IL-1 members in key brain cells that are known to contribute to inflammation after stroke (primarily endothelial cells, microglia and neurons), and to assess the effect of gene deletion on cerebrovascular inflammation and stroke outcome. Our recent preliminary experiments demonstrated that IL-1B (main driver of neuroinflammation after stroke) is expressed in a subset of microglia and infiltrating neutrophils after stroke but the function of microglial- and neutrophil-derived IL-1B in stroke is completely unknown. The aim of the project is to further explore the precise pathophysiological function of IL-1B in stroke by analysing the effect of selective deletion of IL-1B in microglia and neutrophils on stroke outcome, mechanisms of cerebrovascular inflammation, long term vascular repair and functional recovery, using a combination of in vitro and in vivo models of cerebral ischaemia, as well as a large array of powerful molecular, cellular and imaging analytical techniques. The ultimate aim of the project is to provide a better insight into the potential neuroprotective and neuroreparative role of IL-1B during post stroke inflammation for better therapeutic interventions.

白细胞介素-1 (IL-1) 会在中风后引发炎症，导致脑损伤和较差的预后。使用 IL-1 受体拮抗剂 (IL-1Ra) 阻断 IL-1 作用对于临床前中风模型有益，对中风患者的研究表明 IL-1Ra 是安全的，并且可以改善临床结果。重要的是，IL-1 表达为两种同工型：IL-1 α (IL-1a) 和 IL-1 β (IL-1B)，但每种配体在中风中的具体功能完全未知。我们最近建立了新的条件性 IL-1 遗传小鼠模型，以精确识别 IL-1a 和 IL-1B 在中风期间的相对贡献。这可以通过选择性删除已知会导致中风后炎症的关键脑细胞（主要是内皮细胞、小胶质细胞和神经元）中的每个 IL-1 成员来实现，并评估基因删除对脑血管炎症和中风结果的影响。我们最近的初步实验表明，IL-1B（中风后神经炎症的主要驱动因素）在中风后小胶质细胞和浸润性中性粒细胞的子集中表达，但小胶质细胞和中性粒细胞衍生的 IL-1B 在中风中的功能完全未知。该项目的目的是通过结合脑缺血的体外和体内模型以及大阵列分析小胶质细胞和中性粒细胞中IL-1B选择性缺失对中风结局、脑血管炎症机制、长期血管修复和功能恢复的影响，进一步探讨IL-1B在中风中的精确病理生理功能。 强大的分子、细胞和成像分析技术。该项目的最终目标是更好地了解 IL-1B 在中风后炎症期间的潜在神经保护和神经修复作用，以便更好的治疗干预。