Mechanisms Differentiating Dendrite Development from Axon Development

区分树突发育和轴突发育的机制

• 批准号: 7675626
• 负责人: BING YE
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-25 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7675626
• 关键词: Affect; Amyotrophic Lateral Sclerosis; Axon; Biological; Biological Assay; Biological Models; Cells; Cellular biology; Chromosomes, Human, Pair 3; Class; Complement; Defect; Dendrites; Development; Drosophila genus; Embryo; Environment; Fluorescence; Genes; Genetic; Genetic Screening; Goals; Golgi Apparatus; Growth; Hippocampus (Brain); Homologous Gene; Impairment; Institution; Knowledge; Laboratories; Larva; Lead; Life; Lilium; Mammalian Cell; Mammals; Maps; Membrane Protein Traffic; Mentors; Monitor; Morphogenesis; Mutation; Natural regeneration; Nervous System Physiology; Neurobiology; Neurons; Pathogenesis; Pathway interactions; Phase; Play; Process; Proteins; RNA-Binding Proteins; Rattus; Regulation; Research; Research Personnel; Resolution; Rett Syndrome; Role; Signal Pathway; Techniques; Testing; Therapeutic; Training; Training Activity; Transgenic Organisms; Translations; Work; axon growth; base; career; design; fly; genetic regulatory protein; in vivo; interest; intracellular protein transport; mutant; nervous system disorder; neural circuit; novel; post-doctoral training; protein transport; size; skills

My career goal is to understand the mechanisms of neuronal compartmentalization and how this process contributes to nervous system function and to the pathogenesis of neurological disorders. I will pursue this goal by working in an academic institution as an independent investigator. During my postdoctoral training in the laboratory of Dr. Yuh Nung Jan at UCSF, I have been using Drosophila PNS neurons as a model system to study the mechanisms that differentiate the development of dendrite from axon, two major compartments of a neuron. This training complements my doctoral training in vertebrate neurobiology. I plan to combine the strength of Drosophila (in vivo and superb genetics) and cultured rat hippocampal neurons (wellcharacterized cell biology) to study neuronal compartmentalization. The objective of this research is to examine the roles of the secretory pathway in differentiating dendrite and axon development. From a genetic screen in Drosophila, we isolated several mutants (dar mutants) with reduced dendritic arbors but normal axons. Dar2, 3, and 6 regulate the secretory pathway, suggesting that this pathway differentiates dendritic and axonal growth. I propose two aims. First, I will determine cell biological mechanisms through which the secretory pathway differentially controls dendritic and axonal growth. New techniques will be developed to complement existing ones to identify such mechanisms. Membrane traffic through the secretory pathway will be monitored in live wild-type and mutant Drosophila embryos/larvae and cultured hippocampal neurons. Second, I will identify and characterize genes that control the differential development of dendrites and axons by regulating key players of the secretory pathway. Dar7 (genetically interacts with dar2 and 3), darl (genetic interaction untested), and Trailer Hitch (regulates the secretory pathway) will be studied. Their mammalian homologs will be examined in cultured neurons to determine if the mechanisms are conserved in mammals. This research will provide much-needed information for understanding the causes of neurological disorders characterized by preferential damage to dendrites (e.g., Rett's syndrome) or by defective Golgi function (e.g., amyotrophic lateral sclerosis). Such information will also allow the design of therapeutic approaches.

我的职业目标是了解神经元隔室的机制以及该过程如何 有助于神经系统功能和神经系统疾病的发病机理。我会追求这个 通过在学术机构担任独立研究者的目标。在我的博士后培训期间 Yuh Nung Jan博士在UCSF的实验室，我一直在使用果蝇PNS神经元作为模型系统 为了研究区分树突与轴突的机制，两个主要隔室 神经元。这项培训补充了我在脊椎动物神经生物学方面的博士培训。我打算将 果蝇（体内和超级遗传学）和培养的大鼠海马神经元的强度 细胞生物学）研究神经元分室化。 这项研究的目的是检查分泌途径在区分树突中的作用 和轴突开发。从果蝇的遗传筛查中，我们与几个突变体（dar突变体）分离 树突状乔木降低但轴突正常。 DAR2，3和6调节分泌途径，表明 该途径可区分树突状和轴突生长。我提出了两个目标。首先，我将确定单元格 分泌途径差异控制树突状和轴突的生物学机制 生长。将开发新技术来补充现有技术以识别这种机制。 通过分泌途径的膜交通将在现场野生型和突变果蝇中进行监测 胚胎/幼虫和培养的海马神经元。其次，我将确定并表征这些基因 通过调节分泌的主要参与者来控制树突和轴突的差异发展 路径。 DAR7（遗传与DAR2和3相互作用），DARL（未经测试的遗传相互作用）和拖车挂钩 （调节分泌途径）将被研究。他们的哺乳动物同源物将在培养中检查 神经元确定机制是否在哺乳动物中保守。 这项研究将提供急需的信息，以了解神经系统的原因 以对树突的优先损害（例如Rett综合征）或有缺陷的高尔基体为特征的疾病 功能（例如肌萎缩性侧硬化症）。这些信息还将允许设计治疗 方法。