Elucidating the cellular mechanisms by which peroxisomes regulates phagocytosis in innate immune cells

生物体需要一个有效和严密控制的防御系统(免疫系统)来对抗感染。免疫系统的失效会影响每个有机体的生存。生物体的新陈代谢系统现在被认为是正确免疫反应的重要中介。过氧体是细胞内的结构，调节重要的过程，特别是脂代谢和活性物质的解毒。对分离的哺乳动物和酵母细胞的研究表明，过氧化物体是调节不同细胞类型生物体特定功能的重要细胞“开关”。我最近的工作发现了一个以前未知的要求，即过氧化物体在激活果蝇(果蝇)对抗细菌和感染的第一道防线(先天性免疫防御)方面的要求。果蝇通常在实验室里用来研究动物生理学所需的基本细胞过程。在一百多年的科学历史中，果蝇已经被用来了解有机体中不同的细胞和组织是如何发育和功能的，包括天然免疫防御的细胞。我们发现过氧化体是免疫反应的基本介质，特别是我们描述了它们在特殊细胞(昆虫中称为浆细胞，哺乳动物中称为巨噬细胞)中吞噬病原体(吞噬)的要求，以保护我们的身体免受病原体的侵袭。具有不活跃的过氧酶体的浆细胞和巨噬细胞无法清除病原体。我们对过氧化物体在生物体免疫防御中的基本作用的基本理解的下一步是理解过氧化物体是如何“开启和关闭”免疫防御的。我们的研究将解决两个关键问题：1)过氧化体如何影响巨噬细胞对病原体的防御机制2)调节巨噬细胞中依赖于过氧化酶体的吞噬作用的其他“参与者”(细胞信号)是什么？3)过氧化体代谢的变化如何影响吞噬作用和其他免疫反应。 这项拟议的研究将导致1)培训高素质的尖端研究人员和不同职业的可转移技能；2)对先天性免疫反应做出重要的科学贡献，并使过氧化物体在动物生理学中的作用成为核心。 。

Organisms require an effective and tightly controlled defense system (immune system) to fight infections. Failures of the immune system affect every organism's survival. An organism's metabolic system is now recognized as an important mediator of proper immune responses. Peroxisomes are structures within cells that regulate important processes, notably lipid metabolism and the detoxification of reactive species. Studies in isolated mammalian and yeast cells suggest that peroxisomes act as important cellular “switch” that regulate specific functions in different cell type of the organisms. My recent work identified a previously unknown requirement for peroxisomes in activating the first line of defence against bacteria and infection (innate immune defence) in the fruit fly (Drosophila melanogaster). Fruit flies are commonly used in the laboratory to study basic cellular processes that are required for animal physiology. There is over one hundred years of scientific history where fruit flies have been used to understand how the different cells and tissue in the organisms develop and function, including the cells of the innate immune defense. We identified peroxisomes as essential mediators of the immune responses and particularly we described their requirement in engulfing pathogens (phagocytosis) in specialized cells (known as plasmatocytes in insects and macrophages in mammals) that defend our body from pathogens. Plasmatocytes and macrophages with inactive peroxisomes are unable to eliminate the pathogens. The next step in our basic understanding of the essential role of peroxisome in an organism's immune defense is to understand how peroxisomes “turn on and off” the immune defense. Our research will address two critical questions: 1) How peroxisomes affect the mechanisms of defense against pathogens in macrophages 2) What are the other “players”(cellular signaling) that regulate peroxisome-dependent phagocytosis in macrophages? 3) 1) How changes in peroxisome metabolism affects phagocytosis and other immune responses. The proposed research will lead to 1) training of Highly Qualified Personnel in cutting-edge research and transferable skills for diverse careers; and 2) important scientific contributions to the innate immune response and makes a core addition to the roles of peroxisomes in animal physiology. .