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，它们对于保护我们免受致病微生物的侵袭至关重要。它们被认为是应对感染或伤害的第一道防线。中性粒细胞有几种方法可以摧毁微生物，以防止感染传播。它们可以吞噬微生物或产生抗微生物的化学物质。中性粒细胞也可以释放“网”--中性粒细胞胞外陷阱。蚊帐由粘着的DNA网组成，还含有有毒的抗微生物蛋白；蚊帐捕获微生物，防止它们从感染部位扩散。它们还有助于放大炎症和招募额外的免疫细胞。NET的释放必须仔细控制，因为过度的网络形成也会损害我们自己的细胞和组织。事实上，在许多非感染性炎症性疾病中，中性粒细胞经常被过度激活。过度的网络形成被认为会导致自身免疫性疾病，如狼疮、类风湿性关节炎和哮喘，以及癌症和动脉粥样硬化(可能导致中风和心脏病)。如果我们能够了解网络的形成是如何调节的，我们可能会开发出治疗方法，在身体需要预防感染时促进网络形成，或者相反，当它们引起病理性炎症时阻止它们的释放。这项提议的目的是完成正在进行的旨在了解哪些蛋白质控制净释放的研究。我们发现，一些通常控制细胞分裂的蛋白质也参与调节网络的形成。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网络形成中的功能。我们将通过分析调节器与哪些额外的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网络的分子机制。这也将有助于将我的小组建立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.