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患上威胁生命的慢性感染，通常会过早死亡。中性粒细胞通过检测潜在的病原体或炎症区，向它们迁移并吞噬(吞噬)和杀死病原体来发挥这一作用。病原体的杀灭是由一系列抗微生物制剂执行的，其中包括高活性的化学物种和酶，一旦微生物被摄入，这些物质就会释放到附近或中性粒细胞内形成的小消化空泡中。中性粒细胞也可能是许多炎症性疾病的罪魁祸首，如类风湿性关节炎，这一点越来越被接受。在这种情况下，中性粒细胞在炎症部位的过度聚集只会使情况变得更糟，因为大量产生的抗微生物药物会对邻近细胞造成附带损害和炎症。这会导致中性粒细胞进一步聚集，导致一个长期的问题。控制这些中性粒细胞行为的细胞内过程已经被研究了很多年，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在免疫反应中更重要，因此针对它们的药物可能在发挥抗炎作用的同时保留免疫功能。由于目前的抗炎药物有限且有副作用，因此迫切需要此类化合物。我们的项目解决了中性粒细胞内的这些过程如何在健康和疾病中发挥作用。我们专注于这些分子事件中的一个特定的关键角色，称为PI3K-伽马(磷脂酰肌醇3-激酶)，我们在20世纪90年代初首次发现。随着许多大公司筛选/开发新的抑制剂，它现在被认为是新型抗炎药物的潜在靶点。PI3KGamma是由两种蛋白质组成的复合体：P110Gamma和一个P101或P84调节亚基。到目前为止，所有针对PI3K-Gamma开发的药物都旨在抑制p110-Gamma蛋白，因为它总是存在。这两个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有何不同，是否可能或多或少参与促炎性免疫反应，因此可能是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，并了解它们如何不同地工作，以及它们是否提供了更好的药物靶点机会。

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.