Immune cells at the blood-brain interface driving concussion-related symptoms

血脑界面的免疫细胞导致脑震荡相关症状

• 批准号: 2897591
• 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-2897591
• 关键词: Immune; cells; blood; brain; interface

Concussion, or mild traumatic brain injury, affects millions world-wide each year due to motor accidents, falls, assaults, domestic violence, contact sports and war. It is now appreciated that a history of concussion increases the risk of developing long-term emotional and neurocognitive disorders. These include anxiety and depression, as well as neurodegenerative conditions such as Alzheimer's. Critically, we do not know the mechanisms behind long-term negative effects of concussion on brain health.Recent advances in the field of neuroimmunology have opened up our understanding of the connection between the central nervous system and inflammation. The following project will investigate the role of infiltrating immune cells within critical structures at the blood-brain interface and how they contribute to concussive symptoms. We hypothesise that immune responses at these interfaces are key to concussive symptoms after head injury. The interfaces between the periphery and the brain are now under intense scrutiny as hubs of inflammation and potential drivers of brain injury, mood disorders and neurodegenerative disease. Two of the key blood-brain interfaces are the meninges and the choroid plexus. The meninges are a set of protective membranes that surround the brain and the choroid plexus is a structure that produces cerebrospinal fluid and is essential for a variety of brain function. Recent data has shown that the meninges and choroid plexus contain immune cells that are proposed to play important functions in the brain. Surprisingly, little is known of the role of the choroid plexus or meninges and the immune cells within them in concussion.To address this, the project will investigate the role of innate and adaptive lymphocytes in the response to concussive injury in a clinically relevant mouse model. T cells and Innate Lymphoid Cells (ILCs) are potent regulators of the immune response, and are emerging as key players in neuroinflammation while residing in the meningeal membranes and choroid plexus. Moreover, danger signals and soluble factors known to activate lymphocytes, including ILCs, are also known to regulate brain function and recovery after injury, though it remains unknown how lymphocytes contribute to concussion-related symptoms.We predict that a concussive-symptoms are driven by lymphocyte-dependent inflammation in the meninges and choroid plexus and can be targeted to improve outcome after injury. This interdisciplinary project is at crossroads of neuroscience and immunology, reflected by the modelling of brain injury and assessment of emotional behaviour and cognition, while investigating fundamental immune mechanisms driving behavioural deficits.

脑震荡，或轻度创伤性脑损伤，每年影响世界各地数百万人，由于车祸，福尔斯，袭击，家庭暴力，接触性运动和战争。现在意识到，脑震荡史增加了发展长期情绪和神经认知障碍的风险。这些包括焦虑和抑郁，以及神经退行性疾病，如阿尔茨海默氏症。重要的是，我们不知道脑震荡对大脑健康长期负面影响背后的机制。神经免疫学领域的最新进展使我们了解了中枢神经系统和炎症之间的联系。下面的项目将研究浸润免疫细胞在血脑界面关键结构中的作用，以及它们如何导致脑震荡症状。我们假设这些界面的免疫反应是脑损伤后脑震荡症状的关键。外周和大脑之间的界面现在正受到严格的审查，因为它是炎症的中心，也是脑损伤、情绪障碍和神经退行性疾病的潜在驱动因素。两个关键的血脑界面是脑膜和脉络丛。脑膜是一套保护膜，围绕大脑和脉络丛是一个结构，产生脑脊液，是必不可少的各种脑功能。最近的数据表明，脑膜和脉络丛含有免疫细胞，这些免疫细胞被认为在大脑中发挥重要作用。令人惊讶的是，很少有人知道脉络丛或脑膜和免疫细胞在脑震荡中的作用。为了解决这个问题，该项目将调查先天性和适应性淋巴细胞在临床相关小鼠模型中对脑震荡损伤的反应中的作用。T细胞和先天性类淋巴细胞（ILC）是免疫反应的有效调节剂，并且在驻留于脑膜和脉络丛中时正在成为神经炎症的关键参与者。此外，已知激活淋巴细胞的危险信号和可溶性因子，包括ILC，也被认为可以调节脑功能和损伤后的恢复，尽管淋巴细胞如何促进脑震荡相关症状仍然未知，我们预测脑震荡症状是由脑膜和脉络丛中的淋巴细胞依赖性炎症驱动的，可以有针对性地改善损伤后的结果。这个跨学科项目是神经科学和免疫学的交叉点，反映在脑损伤的建模和情绪行为和认知的评估，同时调查驱动行为缺陷的基本免疫机制。