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.

脂质液滴（LDS）是细胞质脂肪储存细胞器，在脂质中具有基本作用 代谢，能量稳态和信号转导。在许多传染病中，他们 积聚在免疫细胞中，可以积极或负面影响生物体的能力 回应感染。尽管有重要进展，但很难评估 免疫引起的LDS整体生物体。果蝇模型的往绩很好 为了提供对先天免疫和LD生物学的一般重要见解。这 拟议的项目利用果蝇研究这些领域之间的交集。 当果蝇幼虫感染细菌时，它们的巨噬细胞样血细胞 （血小细胞）迅速积累LDS。这种反应也可以由细菌细胞壁触发 组件，并严格取决于IMD途径的蛋白质，尤其是NF-KB 转录因子优惠。这是一个非常快速的响应，LD积累可检测到40之内 刺激分钟。对先天免疫和LD的其他方面的深刻保护 苍蝇和哺乳动物之间的生物学表明，这种反应可能至关重要。 但是，由于缺乏机械理解，目前无法测试 反应的生物学意义。该项目将采用两管制的方法 发现免疫诱导的LD形成的潜在机制。我们将确定 哪些组织/细胞NF-KB/Relish功能可以驱动LD形成，并具有组织特异性的RNAi 方法。 IMD途径其他组件的作用也将进行测试以及 响应是否依赖于Relish作为转录激活剂的已知功能。到 确定血细胞LD的形成方式，LD生物发生涉及的各种途径和 营业额将通过实验进行操纵，以及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 工具和智力框架来检验有关功能作用的机理假设 免疫诱导的血细胞LDS，并将照亮巨噬细胞脂质代谢。