MICA: Is PI3Kgamma signalling organised in distinct membrane nano-domains?

中性粒细胞是主要的白色血细胞，参与抵抗细菌和真菌感染。中性粒细胞功能长期缺乏的患者会遭受危及生命的慢性感染，通常会过早死亡。中性粒细胞通过其检测潜在病原体或炎症区域、向其迁移并摄取（吞噬）和杀死病原体的能力来发挥这一作用。病原体杀灭是通过一系列抗微生物剂进行的，包括高度反应性的化学物质和酶，一旦微生物被摄入，这些化学物质和酶就被释放到附近或中性粒细胞内形成的小消化空泡中。越来越多的人认为，中性粒细胞也可能是许多炎症性疾病（如类风湿性关节炎）的关键罪魁祸首。在这些情况下，炎症部位过度的中性粒细胞积聚只会使情况变得更糟，因为抗微生物剂的大量产生会对邻近细胞和炎症造成附带损害。这导致进一步的中性粒细胞募集，导致长期问题。控制这些中性粒细胞行为的细胞内过程已经研究了多年，因为它们在免疫和疾病中起着核心作用。原则上，一些细胞内过程在疾病过程中可能比它们对于免疫应答更重要，因此靶向它们的药物可以作为抗炎剂，同时保留免疫功能。这些化合物是非常需要的，因为目前的抗炎药是有限的，并有副作用。我们的项目解决了中性粒细胞在健康和疾病中的这些细胞内过程如何发挥作用。我们专注于这些分子事件中的一个特定的关键角色，称为PI 3 K-γ（磷酸肌醇3-激酶），我们在20世纪90年代初首次发现。现在被认为是新型抗炎药的潜在靶点，许多大公司正在筛选/开发新的抑制剂。PI 3 K γ被发现为2种蛋白质的复合物; p110 γ和p101或p84调节亚基。迄今为止开发的所有针对PI 3 K-γ的药物都是为了抑制p110-γ蛋白，因为它总是存在的。2个调节亚基的相对作用尚未完全了解：它们在性质和功能方面如何不同，以及是否可能是一个或多或少参与促炎性免疫应答的情况，因此可能是长期开发药物的更好靶点。我们最近的工作（未发表）表明，在小鼠中，p84和p101在中性粒细胞中具有独特的重要作用，在这项资助中，我们希望完善这一想法，并了解它们如何不同地工作，以及它们是否提供更好的机会作为药物靶点。

Neutrophils are the major white blood cell and are involved in fighting bacterial and fungal infections. Patients who have long term deficiencies in neutrophil function suffer from life-threatening chronic infections and usually die early. Neutrophils perform this role through their ability to detect potential pathogens or zones of inflammation, migrate towards them and ingest (phagocytose) and kill the pathogens. Pathogen killing is performed by a battery of anti-microbial agents including highly reactive chemical species and enzymes that are released into the vicinity or into the small digestive vacuole formed inside the neutrophil once microbes have been ingested. It is increasingly accepted that neutrophils can also be key culprits in a number of inflammatory diseases, such as rheumatoid arthritis. In these situations excessive neutrophil accumulation at the site of inflammation only makes things worse as the intense production of anti-microbial agents causes collateral damage to neighbouring cells and inflammation. This results in further neutrophil recruitment, leading to a long-term problem. The intracellular processes that control these neutrophil behaviours have been studied for many years because of their central role in immunity and in disease. In principle, some of the intracellular processes may be more important in the disease processes than they are for the immune response and hence drugs targeting them may act as anti-inflammatories whilst sparing immune function. Such compounds are much needed as current anti-inflmmatories are limited and have side-effects. Our project addresses how these intracellular processes in neutrophil function in both health and disease. We focus on a specifc key player in these molecular events called PI3K-gamma (phosphoinositide 3-kinase) that we first discovered in the early 1990s. It is now accepted to be a potential target for novel anti-inflammatories with many major companies screening/developing new inhibitors. PI3Kgamma is found as a complex of 2 proteins; p110gamma and either a p101 or p84 regulatory subunit. All of the drugs so far developed against PI3K-gamma have been designed to inhibit the p110-gamma protein because it is always present. The relative roles of the 2 regulatory subunits are not completely understood: how they are different in terms of properties and functions and whether it might be case that one is more or less involved in pro-inflammatory v immune responses and may hence may be a better target for the development of drugs in the long term. Our recent work (unpublished) shows that in mice p84 and p101 have unique important roles in neutrophils and in this grant we hope to refine this idea and understand how they work differently and whether they offer better opportunities as drug targets.