Draper pathway in Drosophila glial immune functions

Draper 通路在果蝇胶质细胞免疫功能中的作用

• 批准号: 7014430
• 负责人: Marc R Freeman
• 金额: $ 36.51万
• 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/7014430
• 关键词: Drosophilidae; axon reaction; biological models; biological signal transduction; cell cell interaction; cell morphology; cellular pathology; central nervous system; developmental neurobiology; electron microscopy; glia; immune response; immunogenetics; in situ hybridization; membrane proteins; molecular cloning; molecular genetics; nervous system disorder; neural degeneration; neurons; protein structure function; receptor expression; regulatory gene; sensory receptors; wallerian degeneration

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：神经胶质是神经系统中的主要免疫细胞类型。为了应对神经感染或创伤，它们变得“反应性”，经历了基因表达和形态的刻板印象。但是，对神经损伤或死亡的神经胶质反应的分子细节知之甚少。我们研究果蝇中的神经胶质免疫功能，因为它具有明确的神经胶质亚型，类似于哺乳动物的神经胶质，并且可以接受遗传分析。该提案的重点是果蝇神经胶质的作用和新鉴定的DRPR受体在死亡神经元的神经胶质吞噬中的作用，以及对中枢神经系统中神经损伤的神经胶质反应。 DRPR编码一种吞噬受体，对于神经胶质的神经元细胞尸体必不可少。在切断其轴突后，在神经胶质中，DRPR受体也有效地上调。我们将采用一种分子遗传学方法来了解DRPR在神经损伤中的神经胶质反应，受伤的轴突的神经胶质吞没以及神经创伤后神经元 - 糖相互作用的其他机制。我们的具体目的是：1）表征胚胎中枢神经系统中的draper功能：我们将在果蝇胚胎CN中的细胞尸体去除和神经胶质形态发生中定义DRPR和特定DRPR受体同工型的作用。 2）定义对碎屑在去除受伤轴突中的神经损伤和作用的神经胶质反应：我们将定义神经胶质对神经损伤的形态学和分子变化，并确定DRPR和Glia在去除受伤轴突中的要求。 3）定义WLDS蛋白的细胞和分子作用：沃勒式变性缓慢（WLDS）蛋白可以保护受伤的轴突免受未知机制的变性。我们发现WLD还可以使切断的果蝇轴突免于变性。我们将探索WLDS介导的果蝇轴突的保护，以及WLDS表达对神经损伤反应的后果。神经损伤后神经元 - 神经元通信的机制可能在苍蝇和小鼠中得到良好的保存，因为果蝇神经胶质胶质素也变得反应性，WLD可以保护苍蝇中切断的轴突。表征调节神经元和神经胶质功能对中枢神经系统创伤的基因对于确定治疗中枢神经系统损伤和神经疾病的新途径至关重要。