The Role of 18kDa Translocator Protein (TSPO) in cellular bioenergetics and microglial activation

大脑包含免疫系统的细胞，称为“小胶质细胞”。当神经细胞受损时，小胶质细胞开始活动并被“激活”。小胶质细胞可以以不同的方式被激活。例如，它们可以以一种旨在保护神经细胞免受损伤的方式激活，或者它们可以以一种旨在杀死入侵生物体（如细菌或病毒）的方式激活。许多研究人员现在认为，当小胶质细胞在神经退行性疾病（如阿尔茨海默病，帕金森病甚至多发性硬化症）中被激活时，它们“选择了错误的”激活状态。换句话说，它们以一种对患者无益的方式被激活。在这种状态下，它们不仅不能保护神经细胞，而且实际上会使神经细胞损伤更严重。因此，许多人正试图开发药物来改变小胶质细胞被激活的方式，使它们更有可能以支持和保护神经细胞的方式被激活，而不是使损伤更严重。这一点很重要，因为即使我们还没有完全了解这些疾病的原因，我们仍然可以通过改变小胶质细胞的激活方式来保护神经细胞免受损伤。如果是这样，这将是一个巨大的进步，因为它可能会减缓阿尔茨海默病或帕金森病等疾病的潜在疾病进展，目前我们还没有任何药物可以做到这一点。实验室和动物实验表明，药物结合蛋白质称为转运蛋白（或“TSPO”）可以引起小胶质细胞激活状态的有利变化，并保护神经细胞。但是，我们不知道药物是如何做到这一点的。我们不了解药物如何工作的原因是因为我们甚至不知道蛋白质的作用是什么。理解这一点很重要。如果我们能够了解这些细节，将有助于我们将这些药物转化为有效的药物。这也将帮助我们确定其他潜在的药物靶点。因此，本项目的目的是了解TSPO在小胶质细胞中的作用，并了解结合TSPO的药物如何改变小胶质细胞的激活。本项目将完全基于实验室。我将在伦敦帝国理工学院的阿拉维实验室进行这项工作。我将使用来自于干细胞的小胶质细胞来自于卡迪夫大学艾伦教授的实验室。与其他可用的小胶质细胞相比，这些细胞具有很大的优势。例如，它们来源于人类，因此与动物细胞相比，更有可能反映人类小胶质细胞的功能。

The brain contains cells of the immune system called "microglia". When nerve cells are damaged, microglia spring into action and become "activated". Microglia can become activated in different ways. For example, they can activate in a way designed to protect the nerve cells from damage, or they can activate in a way designed to kill an invading organism, like bacteria or viruses. Many researchers now believe that when microglia become activated in neurodegenerative disease (eg Alzheimer's disease, Parkinson's disease and even multiple sclerosis) they "choose the wrong" activation state. In other words, they become activated in a way that does not benefit the patient. In this state, not only do they fail to protect nerve cells, but they actually make the nerve cell damage worse. Therefore, many people are trying to develop drugs which change the way the microglia become activated, making them more likely to be activated in a way that supports and protects the nerve cells, rather than making the damage worse. This is important, because even though we don't fully understand the causes of these diseases, we might still be able to protecting nerve cells from damage by changing the way microglia activate. It so, this would be a great stride forward, because it might slow the underlying disease progression in diseases such as Alzheimer's disease or Parkinson's disease, and currently we do not have any medications which do this.Laboratory and animal experiments have shown that drugs which bind a protein called Translocator Protein (or "TSPO") can cause a favourable change in activation state in microglia and protect nerve cells. However, we do not understand the way the drugs do this. The reason we do not understand how the drugs work is because we do not even know what the role of the protein is. It is important to understand this. If we can understand these details it will help us to turn these drugs into effective medicines. It will also help us identify other potential drug targets.The aim of this project, therefore, is to understand the role of TSPO in microglia and to understand how drugs which bind TSPO change microglial activation.This project will be entirely laboratory based. I will be carrying out this work in the Alavian laboratory at Imperial College London. I will be using microglial cells derived from stem cells from the laboratory of Professor Allen at Cardiff University. These cells offer great advantages compared to other microglial cells which are available. For example they are derived from humans, and therefore are more likely to reflect how human microglia function compared to animal cells.