Identifying novel strategies to restore the microglial homeostatic phenotype and modulate neuroinflammation

确定恢复小胶质细胞稳态表型和调节神经炎症的新策略

• 批准号: MR/W004372/1
• 负责人: Jing Qiu
• 金额: $ 25.16万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW004372%2F1
• 关键词: Identifying; novel; strategies; restore; microglial

There is currently no cure for dementias, a group of diseases associated with degeneration of the brain and a reduced ability to think, remember or perform tasks. Alzheimer's disease (AD), is the commonest type and collectively they cause a huge financial and emotional burden to society. Failure of several clinical trials for AD points to a need for alternative and innovative approaches. Strong scientific evidence has indicated that a type of brain immune cell called microglia is involved in the initiation and progression of AD. The overarching aim of this project is to identify novel mechanisms to inhibit the progression of AD and other dementias by preventing the harmful changes that occur in microglia that are associated with disease. Microglia are one of a group of different cell types that help support the function of the nerve cells or neurons in the brain. The coordinated interaction of these different cell types is vital for the brain to function correctly. As immune cells, microglia respond to infection in a process called activation. Controlling microglial activation is vitally important because if microglia become incorrectly activated they can start to attack the neurons, something which is thought to happen dementia. In animal models of AD as well as in human AD, the incorrectly activated microglia change their shape and stop making healthy proteins. They also over-react to situations which may add to the disease that is already present. Understanding how microglia become incorrectly activated is therefore critical in finding new treatments for disease because if we can block or reverse the incorrect activation it may improve or prevent disease.Previously it was difficult to study microglia, as microglia become activated and change their properties as soon as they are taken out of the brain. To tackle this technical difficulty, we collaborated with bioinformaticians and invented a novel system in which the incorrect activation of microglia can be studied in the laboratory. Using this novel system, we can grow neurons, astrocytes (another type of brain cell) and microglia together in a dish so that they work together in a similar way to how they do in the brain. We then can study the interactions between these different brain cells in detail. We have discovered that neurons and astrocytes work together to release components that maintain microglial healthy properties and prevent their incorrect activation. This project aims to work out exactly what specific components released by neurons and astrocytes that are responsible for keeping microglial healthy properties and prevent their incorrect activation in order to develop new treatments for disease. We will also use this novel system to test a library of 4000 drugs already known to be safe for use in humans to look for those that maintain microglial healthy properties and prevent their incorrect activation, in order to work out the mechanisms to reveal novel therapeutic targets. This repurposing of known drugs accelerates the translation of these from bench to bedside. This project will lead to potential new treatments for dementia, improving the quality of life of many people and their families affected by dementia.

目前还没有治愈痴呆症的方法，痴呆症是一组与大脑退化和思维、记忆或执行任务能力下降有关的疾病。阿尔茨海默病(AD)是最常见的类型，它们共同给社会造成了巨大的经济和情感负担。AD的几个临床试验的失败表明需要替代和创新的方法。强有力的科学证据表明，一种名为小胶质细胞的大脑免疫细胞参与了AD的发生和发展。该项目的首要目标是确定新的机制，通过防止与疾病相关的小胶质细胞中发生的有害变化来抑制AD和其他痴呆的进展。小胶质细胞是一组不同类型的细胞之一，有助于支持神经细胞或大脑中神经元的功能。这些不同类型的细胞之间的协调互动对大脑的正常运作至关重要。作为免疫细胞，小胶质细胞在一个称为激活的过程中对感染做出反应。控制小胶质细胞的激活至关重要，因为如果小胶质细胞被错误激活，它们可能会开始攻击神经元，这被认为是痴呆症的发生。在阿尔茨海默病动物模型和人类阿尔茨海默病模型中，不正确激活的小胶质细胞改变了它们的形状，停止制造健康的蛋白质。他们还会对可能增加现有疾病的情况做出过度反应。因此，了解小胶质细胞是如何被错误激活的，对于寻找新的疾病治疗方法至关重要，因为如果我们能够阻止或逆转错误的激活，它可能会改善或预防疾病。以前，研究小胶质细胞是困难的，因为小胶质细胞一旦被从大脑中取出，就会被激活并改变其性质。为了解决这一技术难题，我们与生物信息学家合作，发明了一种新的系统，可以在实验室中研究小胶质细胞的错误激活。使用这个新的系统，我们可以在培养皿中一起培养神经元、星形胶质细胞(另一种脑细胞)和小胶质细胞，这样它们就可以像在大脑中一样协同工作。然后我们就可以详细研究这些不同脑细胞之间的相互作用。我们已经发现，神经元和星形胶质细胞共同作用，释放维持小胶质细胞健康属性的成分，并防止它们被错误激活。该项目旨在准确找出神经元和星形胶质细胞释放的哪些特定成分负责保持小胶质细胞的健康特性，并防止它们的错误激活，以开发新的疾病治疗方法。我们还将使用这个新系统来测试一个包含4000种已知可安全用于人类的药物的库，以寻找那些保持小胶质细胞健康特性并防止其错误激活的药物，以便找出揭示新治疗靶点的机制。这种已知药物的再利用加速了这些药物从工作台到床边的转换。该项目将为痴呆症带来潜在的新疗法，改善许多受痴呆症影响的人及其家人的生活质量。