Mechanisms Differentiating Dendrite Development from Axon Development

区分树突发育和轴突发育的机制

• 批准号: 7223870
• 负责人: BING YE
• 金额: $ 9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 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 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7223870
• 关键词: Drosophilidae; Golgi apparatus; RNA binding protein; axon; biochemical evolution; biological signal transduction; cell differentiation; dendrites; developmental genetics; developmental neurobiology; gene expression; gene interaction; genetic regulatory element; hippocampus; laboratory rat; secretion; tissue /cell culture

DESCRIPTION (provided by applicant): 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 (well- characterized 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), dar1 (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.

描述（由申请人提供）： 我的职业目标是了解神经元区室化的机制以及该过程如何影响神经系统功能和神经系统疾病的发病机制。我将通过在学术机构作为独立调查员工作来实现这一目标。在加州大学旧金山分校 Yuh Nung Jan 博士的实验室进行博士后培训期间，我一直使用果蝇 PNS 神经元作为模型系统来研究区分树突和轴突（神经元的两个主要区室）发育的机制。这种培训补充了我在脊椎动物神经生物学方面的博士培训。我计划结合果蝇的优势（体内和卓越的遗传学）和培养的大鼠海马神经元（充分表征的细胞生物学）来研究神经元区室化。本研究的目的是检查分泌途径在分化树突和轴突发育中的作用。从果蝇的遗传筛选中，我们分离出了几种树突乔木减少但轴突正常的突变体（dar 突变体）。 Dar2、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，我将确定分泌途径差异控制树突和轴突生长的细胞生物学机制。将开发新技术来补充现有技术，以识别此类机制。将在活的野生型和突变型果蝇胚胎/幼虫和培养的海马神经元中监测通过分泌途径的膜交通。其次，我将通过调节分泌途径的关键参与者来识别和表征控制树突和轴突差异发育的基因。将研究 Dar7（与 dar2 和 3 进行遗传相互作用）、dar1（未经测试的遗传相互作用）和 Trailer Hitch（调节分泌途径）。他们的哺乳动物同源物将在培养的神经元中进行检查，以确定这些机制在哺乳动物中是否保守。这项研究将为理解以树突优先受损（例如雷特综合征）或高尔基体功能缺陷（例如肌萎缩侧索硬化症）为特征的神经系统疾病的原因提供急需的信息。这些信息也将有助于设计治疗方法。