The role of PtdIns3P in the killing of bacteria and fungi by the neutrophil NADPH oxidase

中性粒细胞是我们体内的白细胞，负责发现、吃掉和杀死有害的微生物。杀死过程的一个重要部分是将大量有毒的氧分子输送到中性粒细胞内一个叫做吞噬体的专门腔室中，吞噬体中含有微生物。这些有毒化学物质是由一种叫做NADPH氧化酶的酶产生的，我们知道它一定很重要，因为发现了一种叫做CGD（慢性肉芽肿病）的罕见疾病，在这种疾病中，携带构成这种酶的六种蛋白质中的一种突变的患者会遭受危及生命的细菌和真菌感染。NADPH氧化酶的启动方式很复杂，因为它必须在食用各种不同微生物时启动但同时它必须？T对周围的身体组织造成太大的伤害。因此，了解NADPH氧化酶是如何工作的，可能会提高我们对某些感染和炎症没有得到妥善处理时出现问题的理解。申请者最近发现，一种名为pi3k的酶可能在调节NADPH氧化酶方面发挥关键作用，这种酶通过在吞噬体周围合成一种名为PtdIns3P的信使分子来调节NADPH氧化酶，他们已经证明这种分子与六种NADPH氧化酶成分中的一种紧密结合。他们建议使用制药行业最近开发的化学物质来特异性阻断pi3k，以评估它们在PtdIns3P合成和NADPH氧化酶功能中的作用。这些实验中的大多数将在从当地志愿者的血液中纯化的中性粒细胞上进行。申请人还创造了突变小鼠，其中编码结合PtdIns3P的氧化酶组分表达的基因被改变以防止这种相互作用。在无病原体的条件下，这些小鼠健康且具有生育能力，他们现在提议评估这种突变对这些小鼠抵抗细菌和真菌感染能力的影响；大多数实验将在从这些动物的骨髓中纯化的中性粒细胞上进行。这个小组在公共领域出版他们的作品方面有着良好的记录，并经常被要求在国际会议上展示他们的作品。它们还与制药业建立了良好的联系，因此这项工作的有益成果应迅速传播。

Neutrophils are white blood cells in our body which are responsible for finding, eating and killing nasty microbes. An important part of the killing process is the delivery of large quantities of toxic oxygen molecules into a specialist chamber inside the neutrophil called a phagosome, which contains the microbe. These toxic chemicals are made by an enzyme called the NADPH oxidase and we know it must be important because of the discovery of a rare disease called CGD (chronic granulomatous disease), where patients carrying mutations in one of the six proteins which make up this enzyme suffer life-threatening bacterial and fungal infections. The way in which the NADPH oxidase is turned on is complicated, because it has to switch on in response to eating a wide variety of different microbes but at the same time it mustn?t cause too much damage to surrounding body tissues. An understanding of how the NADPH oxidase works is thus likely to improve our understanding of what goes wrong when some infections and inflammations are not dealt with properly. The applicants have recently discovered that enzymes called PI3Ks may play a key role in regulating the NADPH oxidase by synthesising a messenger molecule around the phagosome called PtdIns3P, which they have shown binds tightly to one of the six NADPH oxidase components. They propose to use chemicals recently developed by the pharmaceutical industry to specifically block PI3Ks to assess their role in the synthesis of PtdIns3P and NADPH oxidase function. Most of these experiments will be done on neutrophils purified from human blood taken from local volunteers. The applicants have also created mutant mice in which the gene encoding the expression of the oxidase component which binds PtdIns3P has been altered to prevent this interaction. These mice are healthy and fertile when housed under pathogen-free conditions and they now propose to evaluate the effect of this mutation on the ability of these mice to combat bacterial and fungal infections; most of the experiments will be done on neutrophils purified from the bone marrow of these animals. This group has a strong track record in publishing their work in the public domain and are regularly asked to present their work at international conferences. They have also developed good links with the pharmaceutical industry and hence useful results from the work should be quickly disseminated.