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区室化的机制以及这个过程是如何 有助于神经系统功能和神经障碍的发病机制。我会追查下去 目标是在学术机构作为独立调查员工作。在我的博士后培训期间， 在加州大学旧金山分校Yuh Nung Jan博士的实验室，我一直使用果蝇PNS神经元作为模型系统 为了研究树突和轴突两个主要区室的分化机制， 一个神经元。这种训练补充了我在脊椎动物神经生物学方面的博士训练。我计划将联合收割机 果蝇的强度（体内和极好的遗传学）和培养的大鼠海马神经元（良好表征 细胞生物学）来研究神经元区室化。 本研究的目的是探讨分泌途径在树突分化中的作用 和轴突发育。从果蝇的遗传筛选中，我们分离出了几个突变体（dar突变体）， 减少的树突乔木，但正常的轴突。Dar 2、3和6调节分泌途径，表明 该途径区分树突和轴突生长。我提出两个目标。首先，我将确定细胞 分泌途径差异控制树突和轴突的生物学机制 增长将开发新的技术来补充现有的技术，以查明这种机制。 将在活的野生型和突变型果蝇中监测通过分泌途径的膜运输 胚胎/幼虫和培养的海马神经元。其次，我将识别和描述基因， 通过调节分泌的关键参与者来控制树突和轴突的差异发育， 通路Dar 7（与dar 2和3遗传相互作用），dar 1（遗传相互作用未测试），和Trailer Hitch （调节分泌途径）将被研究。它们的哺乳动物同源物将在培养的 神经元，以确定该机制是否在哺乳动物中保守。 这项研究将为了解神经系统疾病的原因提供急需的信息。 以优先损伤树突为特征的疾病（例如，Rett综合征）或高尔基体缺陷 功能（例如，肌萎缩侧索硬化症）。这些信息也将允许设计治疗方案。 接近。