Elucidating the effectors of cell clearance in immunoprivileged organs

阐明免疫豁免器官中细胞清除的效应器

• 批准号: 8205366
• 负责人: Jon Iker Etchegaray
• 金额: $ 2.91万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8205366
• 关键词: Affect; Autoimmune Diseases; Biological; Brain; Cell Death; Cells; Cellular Structures; Cessation of life; Coupled; Data; Development; Disease; Dominant-Negative Mutation; Drosophila genus; Drosophila melanogaster; Effector Cell; Excision; Experimental Models; Eye; Failure; Genes; Genetic; Genetic Screening; Germ Lines; Homeostasis; Immune response; Immunologic Surveillance; Inflammation; Invertebrates; Knowledge; Leukocytes; MAPK8 gene; Mammals; Measures; Mediating; Modeling; Mushroom Bodies; Mutation; Neuroglia; Neurons; Nurses; Oogenesis; Organ; Organism; Ovary; Pathway interactions; Phagocytes; Phagocytosis; Phosphotransferases; Play; Process; Proteins; Resolution; Role; Signal Transduction; Staging; Starvation; Study models; System; Testis Brain; Time; Tissues; Up-Regulation; fly; genetic analysis; human disease; killings; macrophage; mutant; novel; pathogen; prevent; research study; response; tool; tumor

DESCRIPTION (provided by applicant): Project Summary White blood cells do not conduct immune surveillance in certain organs. These organs are termed immunoprivileged. Immunoprivileged organs include the eyes, the testis and the brain, among others. In immunoprivileged organs, cells other than macrophages serve as phagocytes of cell debris. Many diseases affecting immunoprivileged organs involve these resident phagocytes. Furthermore, noxious effects resulting from inflammation of immunoprivileged organs also involve these cells. It is therefore important to understand the mechanisms of the immune response to dead cells triggered by resident phagocytes. We propose to use two immunoprivileged organs in Drosophila melanogaster: the ovary and the brain. The ovaries of flies are immunoprivileged organs where degeneration of the germ line can easily be induced. Once it occurs, somatically derived follicle cells phagocytose the debris resulting from germ line death. The brain of flies is also immunoprivileged and glia remove neuronal cell corpses. Given the genetic tools available in Drosophila, as well the facility of analyzing these organs, makes Drosophila melanogaster a great experimental model for these studies. More specifically, we propose to conduct three different aims to understand the mechanism of cell clearance in immunoprivileged organs. The first aim will consist of identifying the interactions between two effectors of nurse cell clearance in Drosophila ovaries. More specifically we will determine the relationship between two genes that we have found to act in the clearance process. The second aim will be to deduce if the same genetic pathway is involved in the clearance of neuronal corpses by glia. The final aim will be to conduct a genetic screen to identify the negative regulators of the immune response mediated by glia. More specifically we will identify proteins in healthy cells that are involved in this process. Since the mechanisms of cell death and engulfment are highly conserved, these experiments will increase our knowledge of the immune response to dead cells in immunoprivileged organs. It is likely that these findings will have implications in understanding and treating human disease. PUBLIC HEALTH RELEVANCE: Project Narrative Many of the diseases which affect the brain and other organs involve a particular subset of cells which are in charge of removing dead cells from these organs. Understanding how they work can have a great impact on the treatment of disease. This project will investigate how these cells work in a tractable model system.

描述（由申请人提供）：项目摘要白细胞不会在某些器官中进行免疫监测。这些器官被称为免疫动物。免疫动物的器官包括眼睛，睾丸和大脑等。在免疫动物的器官中，巨噬细胞以外的其他细胞充当细胞碎片的吞噬细胞。许多影响免疫保护器官的疾病涉及这些居民的吞噬细胞。此外，由于免疫动力器官的炎症而引起的有害作用也涉及这些细胞。因此，重要的是要了解居民吞噬细胞触发的对死细胞的免疫反应的机制。我们建议在果蝇中使用两个免疫动物器官：卵巢和大脑。果蝇的卵巢是免疫动物的器官，可以很容易地诱导细菌的变性。一旦发生，体面衍生的卵泡细胞吞噬了因生殖系死亡而导致的碎屑。苍蝇的大脑也是免疫养护的，神经胶质消除了神经元细胞尸体。鉴于果蝇中可用的遗传工具以及分析这些器官的设施，使果蝇Melanogaster成为这些研究的绝佳实验模型。更具体地说，我们建议进行三种不同的目的，以了解免疫动力器官中细胞清除的机理。第一个目的将包括确定果蝇卵巢中护士细胞清除率的两个效应因子之间的相互作用。更具体地说，我们将确定在清除过程中发现的两个基因之间的关系。第二个目的是推论是否在神经胶质的神经元尸体中涉及相同的遗传途径。最终目的是进行遗传筛选，以识别神经胶质介导的免疫反应的负调节剂。更具体地说，我们将鉴定出参与此过程的健康细胞中的蛋白质。由于细胞死亡和吞噬的机制是高度保守的，因此这些实验将增加我们对免疫动物器官中死细胞的免疫反应的了解。这些发现可能会对理解和治疗人类疾病产生影响。 公共卫生相关性：项目叙事的许多影响大脑和其他器官的疾病涉及一个特定的细胞子集，这些细胞负责从这些器官中去除死细胞。了解它们的工作方式会对疾病的治疗产生重大影响。该项目将研究这些单元在可聊天模型系统中的工作方式。