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

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考、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巨大的经济和情感负担。几项AD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，一种称为小胶质细胞的脑免疫细胞参与了AD的发生和发展。该项目的总体目标是通过预防与疾病相关的小胶质细胞中发生的有害变化来确定抑制AD和其他痴呆症进展的新机制。小胶质细胞是一组不同的细胞类型之一，有助于支持大脑中神经细胞或神经元的功能。这些不同细胞类型的协调相互作用对大脑正常运作至关重要。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是非常重要的，因为如果小胶质细胞被错误地激活，它们可能会开始攻击神经元，这被认为是发生痴呆症的原因。在AD的动物模型以及人类AD中，错误激活的小胶质细胞改变了它们的形状并停止制造健康的蛋白质。他们还对可能增加已经存在的疾病的情况反应过度。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。以前很难研究小胶质细胞，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特性。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不正确激活。使用这种新系统，我们可以在培养皿中培养神经元、星形胶质细胞（另一种脑细胞）和小胶质细胞，使它们以类似于大脑的方式共同工作。然后我们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特性并防止其不正确激活的成分。该项目旨在确定神经元和星形胶质细胞释放的特定成分，这些成分负责保持小胶质细胞的健康特性，并防止它们的不正确激活，以开发新的疾病治疗方法。我们还将使用这种新系统来测试已知可安全用于人类的4000种药物库，以寻找那些保持小胶质细胞健康特性并防止其不正确激活的药物，以找出揭示新治疗靶点的机制。这种对已知药物的重新利用加速了这些药物从实验室到临床的转变。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庭的生活质量。

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.