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

18kDa 易位蛋白 (TSPO) 在细胞生物能学和小胶质细胞激活中的作用

• 批准号: MR/N008219/1
• 负责人: David Owen
• 金额: $ 127.02万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN008219%2F1
• 关键词: Role; 18kDa; Translocator; Protein; TSPO

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.

大脑含有称为“小胶质细胞”的免疫系统细胞。当神经细胞受损时，小胶质细胞就会开始活动并被“激活”。小胶质细胞可以通过不同的方式被激活。例如，它们可以以保护神经细胞免受损伤的方式激活，或者可以以杀死细菌或病毒等入侵生物体的方式激活。许多研究人员现在认为，当小胶质细胞在神经退行性疾病（例如阿尔茨海默病、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，它们被激活的方式对患者没有好处。在这种状态下，它们不但不能保护神经细胞，反而会使神经细胞的损伤更加严重。因此，许多人正在尝试开发药物来改变小胶质细胞的激活方式，使它们更有可能以支持和保护神经细胞的方式被激活，而不是使损伤变得更严重。这很重要，因为即使我们不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。因此，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，而目前我们没有任何药物可以做到这一点。实验室和动物实验表明，药物可以结合一种称为易位蛋白（或“TSPO”）的蛋白质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。然而，我们不了解药物是如何做到这一点的。我们之所以不了解药物如何发挥作用，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变成有效的药物。它还将帮助我们确定其他潜在的药物靶点。因此，该项目的目的是了解 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。该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亚实验室开展这项工作。我将使用来自卡迪夫大学艾伦教授实验室的干细胞的小胶质细胞。与其他可用的小胶质细胞相比，这些细胞具有巨大的优势。例如，它们源自人类，因此与动物细胞相比，它们更有可能反映人类小胶质细胞的功能。

项目成果

Alzheimer's disease-related transcriptional sex differences in myeloid cells.

• DOI: 10.1186/s12974-022-02604-w
• 发表时间: 2022-10-05
• 期刊: Journal of neuroinflammation
• 影响因子: 9.3

Using team-based revision to prepare medical students for the prescribing safety assessment

• DOI: 10.2147/amep.s204435
• 发表时间: 2019-01-01
• 期刊: ADVANCES IN MEDICAL EDUCATION AND PRACTICE
• 影响因子: 2
• 作者: Field, Samantha M.;Burstow, Nicholas J.;Sam, Amir H.
• 通讯作者: Sam, Amir H.

Additional file 1 of Alzheimer's disease-related transcriptional sex differences in myeloid cells

骨髓细胞中与阿尔茨海默病相关的转录性别差异的附加文件1

• DOI: 10.6084/m9.figshare.21285653
• 发表时间: 2022
• 作者: Coales I

Microglial Activity in People at Ultra High Risk of Psychosis and in Schizophrenia: An [(11)C]PBR28 PET Brain Imaging Study.

• DOI: 10.1176/appi.ajp.2015.14101358
• 发表时间: 2016-01
• 期刊: The American journal of psychiatry
• 作者: Bloomfield PS;Selvaraj S;Veronese M;Rizzo G;Bertoldo A;Owen DR;Bloomfield MA;Bonoldi I;Kalk N;Turkheimer F;McGuire P;de Paola V;Howes OD
• 通讯作者: Howes OD

Cross-platform transcriptional profiling identifies common and distinct molecular pathologies in Lewy body diseases.

• DOI: 10.1007/s00401-021-02343-x
• 发表时间: 2021-09
• 期刊: Acta neuropathologica
• 影响因子: 12.7
• 作者: Feleke R;Reynolds RH;Smith AM;Tilley B;Taliun SAG;Hardy J;Matthews PM;Gentleman S;Owen DR;Johnson MR;Srivastava PK;Ryten M
• 通讯作者: Ryten M