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

生物体需要一个有效和严格控制的防御系统（免疫系统）来对抗感染。免疫系统的故障会影响每一个有机体的生存。生物体的代谢系统现在被认为是适当免疫反应的重要中介。过氧化物酶体是细胞内调节重要过程的结构，特别是脂质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，过氧化物酶体作为重要的细胞“开关”，调节生物体不同细胞类型的特定功能。我最近的工作发现，在激活果蝇（果蝇）抵御细菌和感染的第一道防线（先天免疫防御）时，过氧化物酶体是一种以前未知的需求。在实验室中，果蝇通常被用来研究动物生理所需的基本细胞过程。在一百多年的科学历史中，果蝇被用来了解生物体中不同的细胞和组织是如何发育和运作的，包括先天免疫防御细胞。我们发现过氧化物酶体是免疫反应的重要介质，特别是我们描述了它们在吞噬病原体（吞噬）的特殊细胞（昆虫中的浆细胞和哺乳动物中的巨噬细胞）中保护我们的身体免受病原体侵害的需要。具有失活过氧化物酶体的浆细胞和巨噬细胞不能消灭病原体。我们对过氧化物酶体在生物体免疫防御中的重要作用的基本理解的下一步是了解过氧化物酶体如何“打开和关闭”免疫防御。我们的研究将解决两个关键问题：1)过氧化物酶体如何影响巨噬细胞对病原体的防御机制2)巨噬细胞中调节过氧化物酶体依赖性吞噬的其他“参与者”（细胞信号传导）是什么？3)过氧化物酶体代谢的变化如何影响吞噬和其他免疫反应。

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. .