Regulation of neutrophil functions by cell cycle proteins

细胞周期蛋白对中性粒细胞功能的调节

• 批准号: MR/R02149X/1
• 负责人: Borko Amulic
• 金额: $ 162.14万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR02149X%2F1
• 关键词: Regulation; neutrophil; functions; cell; cycle

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.

中性粒细胞是血液中循环的最常见的免疫细胞；它们占所有白细胞的50%-70%，对于保护我们免受细菌、病毒和其他寄生虫的侵袭至关重要。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，是感染和创伤的“第一反应者”--它们迅速进入受影响的组织以应对微生物威胁。如果中性粒细胞没有到达正确的位置，或者如果他们到达得太晚，身体仍然没有防御能力。一旦找到入侵者，中性粒细胞就有几种方法摧毁它们，以防止感染传播。它们可以吞噬微生物，并通过产生漂白剂等有毒化学物质来杀死它们。中性粒细胞也可以释放“网”--中性粒细胞胞外陷阱。中性粒细胞释放粘连的DNA网络并含有有毒的抗菌蛋白，就形成了蚊帐；蚊帐捕捉微生物并防止它们传播。中性粒细胞用来对抗微生物的有毒抗菌剂是一种危险的货物。它们通过蚊帐的释放必须受到仔细的控制，因为它们也有可能损害我们自己的细胞和组织。事实上，在许多非传染性疾病中，中性粒细胞经常被错误地激活。这些疾病包括各种自身免疫性疾病，如狼疮、类风湿性关节炎和哮喘，也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做出这样或那样的反应知之甚少。这项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了中性粒细胞功能的调节。这是一个令人兴奋的假设，因为它将让我们对中性粒细胞如何执行他们的任务以及事情是如何出错的有一个重大的洞察。由于在癌症的背景下对细胞分裂基因进行了广泛的研究，这也可能意味着某些抗癌药物可以被重新用于治疗中性粒细胞表现出错误行为的疾病。这项在MRC CDA联谊会上概述的研究是跨学科的，并结合了不同生物学领域(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与所有这些领域的研究人员沉浸其中的理想场所，并有机会获得独特的技术专业知识，所有这些在我的奖学金生涯中都将是无价的。

项目成果

Identifying targetable metabolic dependencies across colorectal cancer progression

• DOI: 10.1101/2022.03.23.485483
• 发表时间: 2023-10
• 期刊: bioRxiv
• 作者: D. Legge;Ewelina Stanko;Amy K. Holt;C. Bull;T. Collard;Madhu Kollareddy;Jacob Bellamy;Sarah Groves;Eric H. Ma;E. Hazelwood;D. Qualtrough;B. Amulic;K. Malik;Ann C. Williams;Nicholas Jones;E. Vincent

Exploring disease-causing traits for drug repurposing in critically ill COVID-19 patients: A causal inference approach.

• DOI: 10.1016/j.isci.2023.108185
• 发表时间: 2023-11-17
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Baukmann, Hannes A.;Cope, Justin L.;Bannard, Colin;Schwinges, Alexander R. E. C.;Lamparter, Margaretha R. J.;Groves, Sarah;Ravarani, Charles N. J.;Amulic, Borko;Klinger, Joern E.;Schmidt, Marco F.
• 通讯作者: Schmidt, Marco F.

Neutrophil phenotypes and functions in cancer: A consensus statement.

• DOI: 10.1084/jem.20220011
• 发表时间: 2022-06-06
• 期刊: The Journal of experimental medicine

Investigating a causal role for neutrophil count on P. falciparum severe malaria: a Mendelian Randomization study

调查中性粒细胞计数与恶性疟原虫严重疟疾的因果关系：孟德尔随机研究

• DOI: 10.1101/2023.09.06.23295065
• 发表时间: 2023
• 作者: Constantinescu A

Neutrophil extracellular traps drive inflammatory pathogenesis in malaria

• DOI: 10.1126/sciimmunol.aaw0336
• 发表时间: 2019-10-01
• 期刊: SCIENCE IMMUNOLOGY
• 影响因子: 24.8
• 作者: Knackstedt, Sebastian Lorenz;Georgiadou, Athina;Amulic, Borko
• 通讯作者: Amulic, Borko