The Draper signaling pathway in Drosophila glial immune functions

果蝇胶质细胞免疫功能中的 Draper 信号通路

• 批准号: 7547008
• 负责人: Marc R Freeman
• 金额: $ 35.5万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7547008
• 关键词: Adult; Axon; Biological Models; Brain; Caenorhabditis elegans; Cell Communication; Cells; Cessation of life; Cicatrix; Clinical; Communication; Cytoskeleton; Data; Development; Disease; Drosophila genus; Drosophila melanogaster; EGF gene; Elements; Embryo; Excision; Exhibits; Gene Expression; Genes; Genomics; Gliosis; Goals; Health; Immune; Infection; Injury; Integral Membrane Protein; Knowledge; Mammals; Mediating; Molecular; Molecular Genetics; Morphogenesis; Morphology; Mus; Nervous system structure; Neurodegenerative Disorders; Neuroglia; Neuronal Injury; Neurons; Organism; Pathway Analysis; Pathway interactions; Physiology; Process; Protein Isoforms; Proteins; Regulatory Element; Role; Signal Pathway; Signal Transduction; Surveys; Tissues; Trauma; Traumatic CNS injury; Up-Regulation; Wallerian Degeneration; Work; base; cell type; central nervous system injury; combat; design; fly; gene function; genetic analysis; immune function; in vivo; injured; insight; mutant; nerve injury; nervous system development; nervous system disorder; neuronal cell body; novel; programs; receptor; relating to nervous system; response; tool

Glia are the primary immune cell type in the nervous system. In response to neural infection or trauma they becoming "reactive", undergoing stereotypical changes in gene expression and morphology. However, the molecular details of glial responses to neural injury or death are poorly understood. We study glial immune functions in Drosophila because it has well-defined glial subtypes that resemble mammalian glia, and it is amenable to genetic analysis. This proposal focuses on the role of Drosophila glia and the newly-identified Drpr receptor in glial engulfment of dead neurons, and glial responses to neural injury in the CNS. Drpr encodes an engulfment receptor essential for glial removal of neuronal cell corpses; the Drpr receptor is also potently transcriptionally upregulated in glia after the axons they ensheath are severed. We will take a molecular genetic approach to understand how Drpr functions in glial responses to neural injury, glial engulfment of injured axons, and additional mechanisms of neuron-glia interactions after neural trauma. Our specific aims are: 1) Characterize Draper functions in the embryonic CNS: We will define the role for Drpr and specific Drpr receptor isoforms in cell corpse removal and glial morphogenesis in the Drosophila embryonic CNS. 2) Define glial responses to neural injury and roles for Draper in removing injured axons: We will define morphological and molecular changes exhibited by glia in response to neural injury, and determine the requirements for Drpr and glia in the removal of injured axons. 3) Define the cellular and molecular action of Wlds protein: The Wallerian degeneration slow (Wlds) protein protects injured axons from degeneration by unknown mechanisms. We found that Wlds can also spare severed Drosophila axons from degeneration. We will explore Wlds-mediated protection of Drosophila axons, and the consequences of Wlds expression on glial responses to neural injury. Mechanisms of neuron-glia communication after neural injury are likely well-conserved in flies and mice, since Drosophila glia also become reactive and Wlds can protect severed axons in flies. Characterizing genes that regulate neuronal and glial function in response to CNS trauma is essential to identify new avenues for the treatment of CNS injury and neurological disease.

神经胶质细胞是神经系统中的主要免疫细胞类型。对神经感染或创伤的反应 它们变得“反应性”，在基因表达和形态上经历常规的变化。然而，在这方面， 神经胶质对神经损伤或死亡的反应的分子细节知之甚少。 我们研究果蝇的神经胶质免疫功能，因为它有明确的神经胶质亚型， 哺乳动物的神经胶质，它是服从遗传分析。这项建议的重点是果蝇胶质细胞的作用 以及新发现的Drpr受体在死亡神经元的神经胶质吞噬中以及神经胶质对神经元的反应 CNS损伤。Drpr编码一种吞噬受体，这种受体对于神经胶质清除神经元细胞尸体至关重要; Drpr受体在神经胶质细胞中也有效地转录上调， 切断我们将采用分子遗传学方法来了解Drpr在神经胶质细胞对 神经损伤，损伤轴突的胶质细胞吞噬，以及神经元-胶质细胞相互作用的其他机制， 神经创伤我们的具体目标是： 1)描述德雷珀在胚胎中枢神经系统中的功能：我们将定义Drpr和特定Drpr的作用。 受体亚型在果蝇胚胎中枢神经系统细胞尸体去除和神经胶质形态发生。 2)定义神经胶质对神经损伤的反应和德雷珀在去除损伤轴突中的作用：我们将定义 神经胶质细胞对神经损伤的反应所表现出的形态学和分子学变化，并确定了神经胶质细胞对神经损伤的反应。 Drpr和神经胶质细胞在去除受损轴突中的需求。 3)定义Wlds蛋白的细胞和分子作用：Wallerian变性缓慢（Wlds）蛋白 保护受损的轴突免受未知机制的退化。我们发现野生动物也可以 切断了果蝇的轴突我们将探讨WLDS介导的果蝇保护作用 轴突，以及Wlds表达对神经胶质细胞对神经损伤的反应的后果。 神经损伤后神经元-神经胶质细胞通讯的机制在苍蝇和小鼠中可能是保守的， 因为果蝇神经胶质也变得有反应性，而Wlds可以保护果蝇中切断轴突。表征 调节神经元和神经胶质功能的基因对CNS创伤的反应是识别新的 治疗中枢神经系统损伤和神经系统疾病的途径。