REGULATION OF PHAGOCYTOSIS

白细胞对微生物的吞噬是第一个重要的 在预防全身性感染方面的定义。吞噬小体 含有病原体的生物通常通过一系列的融合而被修饰 和裂解反应，涉及内切溶酶体的隔室 系统，这导致了敌意中的有机体的破坏 吞噬溶酶体的环境。许多病原体，包括致病原 结核病(分枝杆菌)的作用，已经进化出预防机制 吞噬小体到吞噬溶酶体的成熟，从而允许它们的 生死存亡。关于生物化学机制，人们知之甚少 调节裂变和融合反应，调节吞噬小体成熟， 尽管有人假设Rab家族的小G蛋白 磷脂酰肌醇3-激酶(PI-3-Kinase)起着重要作用。 鉴于世界范围内传染性疾病发病率的显著增加 疾病，了解生化机制是至关重要的。 调节吞噬成熟以发展类固醇治疗 接近了。 调节吞噬作用的机制目前正在研究中 遗传上易驯化的阿米巴，盘基网眼菌。这些研究 揭示了吞噬小体成熟的至少4个阶段，包括 形成包含多个颗粒的宽敞的吞噬小体是一个过程 被许多细胞内病原体利用。遗传和生化 已有方法被用来确定GPTase、Rab7和PI 3- 激酶DdPIK1和DdPIK2似乎调节了这一过程。此外， 一种新的Rab，Rabb，也在人类细胞中发现，调节吞噬作用。至 确定调节吞噬小体的生化机制 为使之成熟，提出了以下具体目标。在具体目标1中， 遗传和生化方法将被用来：1)确定PI 3- 蛋白激酶直接作用于吞噬体膜中的磷脂。 以调节同型融合；2)确定Rab7和PI3-Kinase是否 功能偶联；3)鉴定Rab7效应蛋白。具体而言 目的#2，兔在调节中的生化作用机制 吞噬作用和吞噬小体成熟将得到更好的界定。结果是 这些研究应该为以下重要问题提供答案 问题：1)Rab7和PI3-Kinase在功能上和物理上 相互作用：2)PI-激酶和Rab7是否调节细胞内的其他步骤 吞噬小体成熟途径，除了同型融合：3)什么是 与Rab7相互作用的效应蛋白的生化性质； 4)Rabb如何调节粒子的内化？5)如何 Rabb在吞噬小体途径中的其他功能吗？

Phagocytosis of microorganisms by leukocytes represents an important first line of define in the prevention of systemic infections. Phagosomes containing pathogenic organisms are usually modified by a series of fusion and fission reactions, involving compartments of the endo-lysosomal system, which results in the destruction of the organism in the hostile milieu of the phago-lysosome. Many pathogens, including the causative effect of tuberculosis (Mycobacteria), have evolved mechanisms to prevent the maturations of phagosomes to phago-lysosomes, thus allowing for their survival. Little is known concerning the biochemical mechanisms that regulate the fission and fusion reactions regulation phagosome maturation, although it has been hypothesized that the Rab family of small G proteins are phosphatidylinositide 3-kinases (PI 3-kinases) play an important role. Given the significant increase world-wide in the incidence of infectious diseases, it is critical to understand the biochemical mechanisms regulating phagocytosis maturation in order to develop ratione therapeutic approaches. The mechanism regulating phagocytosis are currently being investigated in the genetically tractable amoeba, Dictyostelium discoideum. These studies have revealed at least 4 stages in phagosomal maturation, including the formation of spacious phagosomes containing multiple particles, a process exploited by many intracellular pathogens. Genetic and biochemical approaches have been used to determine that a GPTase, Rab7, and the PI 3- kinases, DdPIK1 and DdPIK2, appear to regulated this process. Furthermore, a novel Rab, RabB, also found in humans cells, regulated phagocytosis. To determine the biochemical mechanisms that operate to regulate phagosomal maturation, the following specific aims are proposed. In specific aim#1, genetic and biochemical approaches will be used to: 1) determine if PI 3- kinases act directly by phosphorylating lipids in the phagosome membrane to regulate homotypic fusion; 2) determine if Rab7 and PI 3-kinases are functionally coupled and 3) identify Rab7 effector proteins. In specific aim #2, the biochemical mechanisms of action of RabB in regulating phagocytosis and phagosomal maturation will be better defined. The results from these studies should supply answers to the following important questions: 1) do Rab7 and PI 3-kinase functionally and physically interact: 2) do PI-kinases and Rab7 regulated other steps in the phagosomal maturation pathway, in addition to homotypic fusion: 3) what is the biochemical nature of the effector proteins that interact with Rab7; 4) how does RabB regulate internalization of particles and 5) how does RabB function elsewhere in the phagosomal pathway?