Immune-induction of lipid droplets in Drosophila larval hemocytes

果蝇幼虫血细胞脂滴的免疫诱导

• 批准号: 10319625
• 负责人: MICHAEL Andreas WELTE
• 金额: $ 19.68万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-16 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10319625
• 关键词: Address; Adipose tissue; Animals; Anti-Bacterial Agents; Bacteria; Bacterial Proteins; Biogenesis; Biological; Biological Models; Biological Process; Biological Testing; Biology; Blood Cells; Cell Wall; Cells; Communicable Diseases; Cultured Cells; Dependence; Disease; Dorsal; Drosophila genus; Eicosanoids; Escherichia coli; Exposure to; Family; Family member; Fat Body; Fatty Acids; Fatty acid glycerol esters; Future; Gene Expression; Genes; Gram-Negative Bacteria; Hemocytes; Hemolymph; Homeostasis; Hour; Immune; Immune signaling; Immunity; Infection; Inflammatory; Intestines; Larva; Lead; Leukocytes; Lipids; Literature; Mammals; Mediating; Metabolic; Modeling; NF-kappa B; Natural Immunity; Nervous system structure; Nuclear; Organelles; Organism; Outcome; Pathway interactions; Pattern; Pattern recognition receptor; Peptidoglycan; Phagocytosis; Process; Proteins; RNA Interference; Reporting; Role; Signal Transduction; Signaling Protein; Speed; Stimulus; System; Testing; Tissues; Transcription Coactivator; Triglycerides; Whole Organism; antimicrobial peptide; base; fighting; fly; follow-up; fungus; immune function; in vivo; injured; insight; knock-down; lipid metabolism; macrophage; microbial; mutant; negative affect; novel; pathogen; response; tool; transcription factor

Lipid droplets (LDs) are cytoplasmic fat storage organelles with fundamental roles in lipid metabolism, energy homeostasis, and signal transduction. In many infectious diseases, they accumulate in immune cells and can positively or negatively affect the ability of the organism to respond to infection. Despite important advances, it is difficult to assess the relevance of immune-induced LDs for the organism as a whole. Drosophila models have a great track record for providing generally important insights into both innate immunity and LD biology. The proposed project takes advantage of Drosophila to study the intersection between these fields. When Drosophila larvae are infected with bacteria, their macrophage-like blood cells (hemocytes) rapidly accumulate LDs. This response can also be triggered by bacterial cell wall components and depends critically on proteins of the Imd pathway, in particular the NF-kB transcription factor Relish. It is a very rapid response, with LD accumulation detectable within 40 minutes of stimulation. The deep conservation of other aspects of innate immunity and LD biology between flies and mammals suggests that this response could be broadly important. However, because a mechanistic understanding is lacking, it is currently impossible to test the biological significance of the response. This project will employ a two-pronged approach to uncover the underlying mechanisms of immune-induced LD formation. We will determine in which tissues/cells NF-kB/Relish functions to drive LD formation, with a tissue-specific RNAi approach. The role of other components of the Imd pathway will also be tested as well as whether the response relies on the known function of Relish as a transcriptional activator. To determine how the hemocyte LDs form, various pathways involved in LD biogenesis and turnover will be manipulated experimentally and the consequences for LD accumulation examined, both in the basal state and after immune induction. These studies will generate the tools and intellectual framework to test mechanistic hypotheses about the functional role of immune-induced hemocyte LDs and will illuminate macrophage lipid metabolism in general.

脂滴（Lipid droplets，LDs）是细胞质中的脂肪储存细胞器，在脂质代谢中起着重要作用 代谢、能量稳态和信号转导。在许多传染病中， 在免疫细胞中积累，并能积极或消极地影响生物体的能力， 应对感染。尽管取得了重要进展，但很难评估 免疫诱导的LD作为一个整体的有机体。果蝇模型有很好的记录 为先天免疫和LD生物学提供了普遍重要的见解。的 拟议的项目利用果蝇来研究这些领域之间的交叉。 当果蝇幼虫被细菌感染时，它们的巨噬细胞样血细胞 （血细胞）快速积累LD。这种反应也可以由细菌细胞壁触发 主要依赖于Imd途径的蛋白质，特别是NF-kB。 转录因子Relish。这是一个非常迅速的反应，LD积累检测40 分钟的刺激先天免疫和LD其他方面的深度保护 果蝇和哺乳动物之间的生物学关系表明，这种反应可能具有广泛的重要性。 然而，由于缺乏机械的理解，目前不可能测试 反应的生物学意义。该项目将采用双管齐下的方法， 揭示免疫诱导LD形成的潜在机制。我们将在 其中组织/细胞NF-kB/Relish的功能是通过组织特异性RNAi来驱动LD的形成， approach. IMD途径的其他组分的作用也将被测试，以及 该反应是否依赖于Relish作为转录激活因子的已知功能。到 确定血细胞LD如何形成，LD生物发生中涉及的各种途径， 营业额将被操纵实验和LD积累的后果 在基础状态和免疫诱导后检查。这些研究将产生 工具和知识框架，以测试有关功能作用的机制假设， 免疫诱导的血细胞LD，并将阐明一般巨噬细胞脂质代谢。