Mechanisms of apoptotic neuron clearance in the peripheral nervous system

周围神经系统凋亡神经元清除机制

• 批准号: 8286335
• 负责人: Bruce D Carter
• 金额: $ 33.44万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8286335
• 关键词: Address; Alzheimer' s Disease; Antibodies; Apoptosis; Apoptotic; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Binding; Biological Assay; Caenorhabditis elegans; Cell Count; Cells; Complex; Consensus; Data; Defect; Development; Disease; Drosophila genus; Dynamin; Dynamin 2; Ectopic Expression; Embryonic Development; Endocytosis; Etiology; Excision; Extracellular Domain; Failure; Ganglia; Genes; Goals; Health; Hela Cells; Homologous Gene; Immune system; In Situ Hybridization; In Vitro; Inflammation; Inflammatory Response; Injury; Lead; Measures; Molecular; Mus; Mutate; Nervous system structure; Neurons; Neuropathy; Pathology; Pathway interactions; Pattern; Peripheral Nervous System; Phagocytosis; Process; Protein Isoforms; Proteins; Receptor Cell; Role; Signal Transduction; Spinal Ganglia; Staging; Stroke; Testing; Trefoil Motif; in vivo; insight; knock-down; mutant; nerve injury; neuron loss; neuropathology; prevent; receptor; reconstitution; response; satellite cell; scavenger receptor; sciatic nerve

DESCRIPTION (provided by applicant): During the normal development of the mammalian nervous system there is extensive programmed cell death, which is required for establishing proper cell numbers and connections. A number of pathologies, such as nerve injury and diseases such as Alzheimer's can lead to apoptosis as well. The resulting neuronal corpses must be efficiently removed in order to prevent an immune system response, which can involve inflammation and autoimmunity. Indeed, a number of autoimmune diseases have been associated with a failure to properly clear dead cells. Unfortunately, the molecular mechanisms underlying this phagocytic process are poorly understood, particularly in the nervous system. In the peripheral nervous system, there is virtually nothing known about how the dead neurons are removed. Hence, the overall goal of this study is to elucidate the cellular and molecular mechanisms underlying the phagocytosis of apoptotic neurons in the developing peripheral nervous system. In C. elegans, two pathways involved in apoptotic cell clearance have been genetically defined; the first includes CED-1, -6, -7 and -10 and the second CED-2, -5, -10 and -12. The mammalian homologs of most of these genes have been identified; however, for CED-1, which is thought to function as a receptor for cell corpses, there have been several possible homologs proposed, including MEGF10, LRP-1 and the scavenger receptor SREC, but no consensus has been reached. Whether these pathways participate in the removal of apoptotic neurons during mammalian development is not known. Our preliminary data suggest that MEGF10 and a related protein, Jedi, are required for dorsal root ganglia (DRG) neuron engulfment and that satellite cells in the ganglia express these genes and are responsible for the removal of the dead neurons. Therefore, we hypothesize that the phagocytosis of dead DRG neurons during embryogenesis by satellite cells involves the putative CED-1 homologs MEGF10 and Jedi. To address this hypothesis we propose the following specific aims: (1) Determine whether MEGF10 and/or Jedi functions as a receptor for apoptotic neuron engulfment by satellite cells; (2) Define the expression pattern of MEGF10 and Jedi in the developing mouse; (3) Determine whether Jedi or MEGF10 signal through homologs of the CED-1 pathway to regulate Rac; (4) Determine whether Jedi is required in vivo for neuronal corpse engulfment during development. Elucidating the mechanisms by which apoptotic neurons are phagocytosed will not only enhance our understanding of the development of the mammalian nervous system, but will likely provide important insights into the etiology of autoimmune neuropathies. PUBLIC HEALTH RELEVANCE: Neuronal cell death is a normal part of the development of the mammalian nervous system, required for establishing proper cell numbers and connections, but can also occur in various injuries and neuropathologies; for example, stroke, Alzheimer's disease and chemotherapeutic treatment. The failure to remove dead cells can lead to an inflammatory response and autoimmune diseases; however, how these dead neurons are cleared is not well understood and in the peripheral nervous system is completely unknown. The goal of this application is to determine the cellular and molecular mechanisms underlying the clearance of dead neurons in the developing peripheral nervous system.

描述（由申请人提供）：在哺乳动物神经系统的正常发育期间，存在广泛的程序性细胞死亡，这是建立适当的细胞数量和连接所必需的。许多病理，例如神经损伤和诸如阿尔茨海默氏症之类的疾病也可能导致凋亡。为了防止免疫系统反应，必须有效去除产生的神经元尸体，这可能涉及炎症和自身免疫性。实际上，许多自身免疫性疾病已经与未正确清除死细胞有关。不幸的是，这种吞噬过程的分子机制知之甚少，尤其是在神经系统中。在周围神经系统中，关于如何去除死亡神经元几乎一无所知。因此，这项研究的总体目标是阐明发育中神经神经系统中凋亡神经元吞噬作用的细胞和分子机制。在秀丽隐杆线虫中，已经在遗传上定义了凋亡细胞清除率的两种途径。第一个包括CED -1，-6，-7和-10以及第二个CED -2，-5，-10和-12。这些基因大多数的哺乳动物同源物已被鉴定出来。但是，对于被认为充当细胞尸体受体的CED-1，提出了几种可能的同源物，包括MEGF10，LRP-1和清除剂受体SREC，但尚未达成共识。这些途径是否参与哺乳动物发育过程中凋亡神经元的去除。我们的初步数据表明，MEGF10和相关的蛋白质JEDI是背根神经（DRG）神经元吞噬所必需的，而神经节中的卫星细胞表达了这些基因，并负责去除死去的神经元。因此，我们假设卫星细胞在胚胎发生过程中死亡DRG神经元的吞噬作用涉及推定的CED-1同源物MEGF10和JEDI。为了解决这一假设，我们提出了以下特定目的：（1）确定MEGF10和/或JEDI是否作为卫星细胞吞噬凋亡神经元的受体； （2）在发育中的鼠标中定义MEGF10和JEDI的表达模式； （3）确定Jedi或MeGF10是否通过调节RAC的CED-1途径的同源物来确定是否信号； （4）确定在发育过程中是否需要在体内进行绝地理命。阐明凋亡神经元被吞噬的机制不仅会增强我们对哺乳动物神经系统发展的理解，而且可能会提供对自身免疫性神经病病因的重要见解。公共卫生相关性：神经元细胞死亡是哺乳动物神经系统发展的正常部分，建立适当的细胞数量和连接所需，但也可能发生在各种伤害和神经病理学中；例如，中风，阿尔茨海默氏病和化学治疗。无法去除死细胞会导致炎症反应和自身免疫性疾病。但是，如何清除这些死去的神经元尚不清楚，在周围神经系统中，完全未知。该应用的目的是确定发育中周围神经系统中死去神经元清除的基础的细胞和分子机制。