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

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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.