MRC TS Award: Regulation of neutrophil functions by cell cycle proteins

中性粒细胞是血液中最丰富的免疫细胞，它们对保护我们免受致病微生物的侵害至关重要。它们被认为是应对感染或伤害的“第一道防线”。中性粒细胞有几种破坏微生物的方法来防止感染的传播。它们可以吞噬微生物或产生抗菌化学物质。中性粒细胞也可以释放“NETs”——中性粒细胞胞外陷阱。网络由具有粘性的DNA网组成，也含有有毒的抗菌蛋白；蚊帐捕获微生物并防止它们从感染部位扩散出去。它们还有助于扩大炎症并招募额外的免疫细胞。NET的释放必须小心控制，因为过量的NET形成也会损害我们自己的细胞和组织。事实上，中性粒细胞在许多非感染性炎症性疾病中经常被过度激活。过度的NET形成被认为会导致自身免疫性疾病，如狼疮、风湿性关节炎和哮喘，以及癌症和动脉粥样硬化（可导致中风和心脏病发作）。如果我们能够理解NET的形成是如何被调节的，我们就有可能开发出一种治疗方法，在身体需要预防感染时促进NET的形成，或者相反，在它们引起病理性炎症时阻止它们的释放。本提案的目的是完成正在进行的旨在了解哪些蛋白质控制NET释放的研究。我们发现一些通常控制细胞分裂的蛋白质也参与调节NET的形成。我们现在建议进行详细的研究，以确切地了解这些蛋白质在NET形成中的作用。我们将通过分析调节因子与哪些其他蛋白质相互作用，以及它们影响细胞生物学的哪些方面来做到这一点。完成这些目标将使我们更好地理解NETs的分子机制。这也将有助于使我的小组成为中性粒细胞生物学领域的国际专家，使我们能够解决重要的全球健康问题。

Neutrophils are the most abundant immune cells in the blood and they are essential for defending us against disease-causing microbes. They are considered the 'first line of defence' in response to infection or wounding. Neutrophils have several ways of destroying microbes to prevent the infection from spreading. They can engulf microbes or produce antimicrobial chemicals. Neutrophils can also release "NETs" - Neutrophil Extracellular Traps. NETs consist of webs of DNA that are adhesive and also contain toxic antimicrobial proteins; NETs trap microbes and prevent them from spreading away from the site of infection. They also help to amplify inflammation and to recruit additional immune cells.NET release must be carefully controlled because excessive NET formation can also damage our own cells and tissues. In fact, neutrophils are often hyperactivated in many non-infectious inflammatory diseases. Excessive NET formation is thought to contribute to autoimmune diseases such as lupus, rheumatoid arthritis and asthma, as well as cancer and atherosclerosis (which can cause stroke and heart attack).If we could understand how NETs formation is regulated, we could potentially develop therapies to boost NET formation when the body needs to prevent infections or, conversely, to block their release when they are causing pathological inflammation. The aim of this proposal is to complete undergoing studies that aim to understand which proteins control NET release. We discovered that some proteins that normally control cell division are also involved in regulating NET formation. We now propose to undertake detailed studies to understand exactly how these proteins function in NET formation. We will do this by analysing which additional proteins the regulators interact with, and what aspects of cellular biology they affect.Completing these aims will give us a better understanding of the molecular mechanism of NETs. It would also help to establish my group as international experts in the field of neutrophil biology, allowing us to tackle important global health issues.