Regulation of neutrophil functions by cell cycle proteins

中性粒细胞是血液循环中最常见的免疫细胞；它们占所有白细胞的50-70%，对保护我们免受细菌、病毒和其他寄生虫的侵害至关重要。它们存在于包括鱼类、鸟类和哺乳动物在内的所有脊椎动物中，是感染和伤害的“第一反应者”——它们迅速进入受影响的组织，以应对微生物的威胁。如果中性粒细胞没有到达正确的位置，或者到达得太晚，身体就会失去防御能力。一旦它们找到了入侵者，中性粒细胞有几种方法来摧毁它们，以防止感染扩散。它们可以吞噬微生物，并通过产生漂白剂等有毒化学物质杀死微生物。中性粒细胞也可以释放“NETs”——中性粒细胞胞外陷阱。当中性粒细胞释放具有粘性且含有有毒抗菌蛋白的DNA网时，net就会形成；蚊帐捕获微生物并防止它们扩散。中性粒细胞用来对付微生物的有毒抗菌剂是一种危险的货物。它们通过神经网络的释放必须小心控制，因为它们也有可能损害我们自己的细胞和组织。事实上，中性粒细胞在许多非传染性疾病中经常被错误地激活。这些疾病包括各种自身免疫性疾病，如狼疮、风湿性关节炎和哮喘，还包括癌症和动脉粥样硬化（导致中风或心脏病发作）。尽管它们与疾病相关，但我们对中性粒细胞如何“决定”以这样或那样的方式作出反应知之甚少。本研究的目的是了解哪些基因控制中性粒细胞的行为以及来自环境的信号如何调节中性粒细胞的行为方式。我发现通常控制细胞分裂的基因也参与调节中性粒细胞的功能。这是一个令人兴奋的假设，因为它可以让我们深入了解中性粒细胞是如何完成任务的，以及事情是如何出错的。由于细胞分裂基因在癌症的背景下被广泛研究，这也可能意味着某些癌症药物可以重新用于治疗中性粒细胞表现出错误行为的疾病。MRC CDA奖学金概述的研究是跨学科的，结合了生物学不同领域（免疫学、细胞分裂和微生物学）的概念。布里斯托尔大学将是一个理想的地方，与来自所有这些领域的研究人员沉浸在一起，并有机会获得独特的技术专长，所有这些对我的奖学金都是无价的。

Neutrophils are the most common immune cells circulating in the blood stream; they account for 50-70% of all white blood cells and are essential for defending us from bacteria, viruses and other parasites. They are found in all vertebrates, including fish, birds and mammals, and are the 'first-responders' to infections and wounding - they move rapidly into the affected tissues to deal with the microbial threat. If neutrophils do not arrive to the correct place, or if they arrive too late, the body remains defenceless. Once they have located the invaders, neutrophils have several ways of destroying them to prevent the infection from spreading. They can engulf microbes and kill them by producing toxic chemicals such as bleach. Neutrophils can also release "NETs" - Neutrophil Extracellular Traps. NETs are made when neutrophils release webs of DNA that are adhesive and contain toxic antimicrobial proteins; NETs trap microbes and prevent them from spreading.The toxic antimicrobials that neutrophils use against microbes are a dangerous cargo. Their release via NETs must be carefully controlled because they also have the potential to damage our own cells and tissues. In fact, neutrophils are often incorrectly activated in many non-infectious diseases. These include various autoimmune diseases, such as lupus, rheumatoid arthritis and asthma, but also cancer and atherosclerosis (which leads to stroke or heart attack).Despite their relevance for disease, we know very little about how neutrophils 'decide' to react one way or another. The aim of this Fellowship is to understand which genes control neutrophil behaviour and how signals from the environment regulate the way in which a neutrophil acts. I found that genes which normally control cell division are also involved in regulating neutrophil functions. This is an exciting hypothesis because it would give us a major insight into how neutrophils carry out their tasks and how things go awry. Since cell division genes are extensively studied in the context of cancer, it might also mean that certain cancer drugs could be re-purposed to treat diseases where neutrophils show faulty behaviour.The research outlined in this MRC CDA Fellowship is interdisciplinary and combines concepts from different areas of biology (immunology, cell division and microbiology). The University of Bristol will be an ideal place to be immersed with researchers from all of these fields, and to have access to unique technical expertise, all of which will be invaluable throughout my Fellowship.