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: 7729872
• 负责人: Bruce D Carter
• 金额: $ 33.91万
• 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/7729872
• 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; Hela Cells; Homologous Gene; Immune system; In Situ Hybridization; In Vitro; Inflammation; Inflammatory Response; Injury; Lead; Measures; Molecular; Mus; Mutate; Myxoid cyst; 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; public health relevance; 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过程中，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，如神经损伤和疾病，如阿尔茨海默氏症，也可以导致细胞凋亡。产生的神经元尸体必须有效地去除，以防止免疫系统反应，这可能涉及炎症和自身免疫。事实上，许多自身免疫性疾病都与未能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，特别是在神经系统中。在周围神经系统中，几乎没有人知道死亡的神经元是如何被移除的。因此，本研究的总体目标是阐明在发育中的周围神经系统中吞噬凋亡神经元的细胞和分子机制。In C.在线虫中，涉及凋亡细胞清除的两种途径已经在遗传上被定义;第一种包括CED-1、-6、-7和-10，第二种包括CED-2、-5、-10和-12。大多数这些基因的哺乳动物同源物已被确定;然而，对于CED-1，它被认为是作为细胞尸体的受体，已经提出了几种可能的同源物，包括MEGF 10，LRP-1和清道夫受体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尚不清楚。我们的初步数据表明，MEGF 10和相关蛋白质Jedi是背根神经节（DRG）神经元吞噬所必需的，神经节中的卫星细胞表达这些基因，并负责去除死亡的神经元。因此，我们推测，卫星细胞在胚胎发生过程中吞噬死亡的DRG神经元涉及假定的CED-1同源物MEGF 10和Jedi。为了解决这一假设，我们提出了以下具体目标：（1）确定MEGF 10和/或Jedi是否作为卫星细胞吞噬凋亡神经元的受体发挥作用;（2）确定MEGF 10和Jedi在发育中小鼠中的表达模式;（3）确定Jedi或MEGF 10是否通过CED-1通路的同源物来调节Rac;（4）确定在发育过程中，体内神经元尸体吞噬是否需要Jedi。阐明凋亡神经元被吞噬的机制不仅将增强我们对哺乳动物神经系统发育的理解，而且可能为自身免疫性神经病的病因学提供重要的见解。公共卫生相关性：神经元细胞死亡是哺乳动物神经系统发育的正常部分，是建立适当的细胞数量和连接所需的，但也可能发生在各种损伤和神经病理中;例如，中风、阿尔茨海默病和化疗。未能清除死细胞可能导致炎症反应和自身免疫性疾病;然而，这些死神经元如何被清除尚不清楚，并且在外周神经系统中完全未知。本申请的目的是确定在发育中的外周神经系统中死亡神经元的清除的细胞和分子机制。