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

中性粒细胞是主要的白细胞，参与对抗细菌和真菌感染。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，通常会早死。中性粒细胞通过其检测潜在病原体或炎症区域的能力来发挥这一作用，向它们迁移并吞噬并杀死病原体。杀灭病原体是由一系列抗微生物剂完成的，包括高活性的化学物质和酶，一旦微生物被摄入，它们就会被释放到附近或中性粒细胞内部形成的小消化液泡中。越来越多的人认为中性粒细胞也可能是许多炎症性疾病（如类风湿关节炎）的关键罪魁祸首。在这些情况下，炎症部位的过量中性粒细胞积累只会使情况变得更糟，因为抗菌剂的大量产生会对邻近细胞造成附带损害和炎症。这导致进一步的中性粒细胞募集，导致长期的问题。控制这些中性粒细胞行为的细胞内过程已被研究多年，因为它们在免疫和疾病中的核心作用。原则上，一些细胞内过程在疾病过程中可能比它们对免疫反应更重要，因此针对它们的药物可能在保留免疫功能的同时起到抗炎作用。由于目前的抗炎药有限且有副作用，因此非常需要这种化合物。我们的项目解决了这些中性粒细胞在健康和疾病中如何发挥作用的细胞内过程。我们专注于在这些分子事件中称为pi3k - γ（磷酸肌肽3-激酶）的特定关键参与者，我们在20世纪90年代初首次发现。现在，随着许多大公司筛选/开发新的抑制剂，它被认为是新型抗炎药的潜在靶点。PI3Kgamma是由两种蛋白质组成的复合物；p110和p101或p84调控亚基。到目前为止，所有针对pi3k - γ的药物都是为了抑制p110- γ蛋白而设计的，因为它总是存在的。这两种调节亚基的相对作用尚不完全清楚：它们在性质和功能方面是如何不同的，以及是否可能存在一种或多或少参与促炎v免疫反应的情况，从而可能成为长期药物开发的更好靶点。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，了解它们如何不同地起作用，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.