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The role of the secretory pathway in ethanol-induced neural tissue injury

分泌途径在乙醇诱导的神经组织损伤中的作用

基本信息

批准号：
8699608
负责人：
BING YE
金额：
$ 17.91万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8699608
关键词：
Affect Alcohol consumption Applied Genetics Axon Biological Biological Assay Candidate Disease Gene Caspase Cells Defect Dendrites Development Diet Drosophila genus Endoplasmic Reticulum Ethanol Fetal Alcohol Exposure Fetal Alcohol Syndrome Foundations Gene Proteins Genetic Techniques Goals Golgi Apparatus Growth Human Injury Insecta Investigation Knowledge Laboratories Larva Lead Lipids Mammals Mediating Membrane Membrane Proteins Mental Retardation Molecular Analysis Morphology Nervous system structure Neurons Organelles Pathway interactions Proteins Research Resolution Role Signal Transduction Structural Protein Structure System Testing Therapeutic Tissues alcohol effect alcohol exposure alcohol research base cell type cellular imaging design endoplasmic reticulum stress feeding genetic analysis glycosylation human disease in vivo innovation nerve injury neurodevelopment neuron development prevent public health relevance relating to nervous system response trafficking

项目摘要

DESCRIPTION (provided by applicant): Damage to neuronal dendrites is a key component of ethanol-induced neural injury. However, the mechanisms underlying ethanol-induced dendrite defects are poorly understood. Knowledge of these mechanisms is essential if we are to understand the effects of alcohol on neuronal development and design strategies for preventing the damaging effects of ethanol on developing neurons. Our long-term goals are to define the mechanisms underlying dendrite and axon development and to determine how defects in dendrites and axons lead to human diseases. The objective of the proposed research is to delineate the mechanisms underlying ethanol-induced dendrite growth defects. Previous studies have demonstrated the importance of the secretory pathway in dendrite development. Although ethanol is known to cause ER stress in various cell types, its effects on ER and Golgi, which are pivotal for the trafficking and glycosylation of membrane and secreted proteins and for cellular signaling, is much less understood. The applicant has established a unique system that is genetically tractable for studying the neuronal secretory pathway in Drosophila. The central hypothesis is that ethanol-induced ER stress leads to ER reorganization and Golgi fragmentation and consequently reduces dendritic growth. This hypothesis is based on preliminary findings from the applicant's laboratory. This hypothesis will be tested by pursuing two specific aims: 1) Identify the mechanism underlying ethanol-induced ER and Golgi defects in neurons; 2) Identify the mechanism underlying ethanol-induced dendrite growth defects. Under the first aim, genetic techniques and cell biological assays, which have been established as feasible in the applicant's lab, will be applied to delineate the roles of ER stress and related responses in ethanol-induced defects in ER and Golgi. Under the second aim, the applicant will take advantage of his expertise in analyzing dendrite development to delineate the roles of ER stress and Golgi fragmentation in ethanol-induced dendrite growth. The results of the proposed research are expected to define a causal relationship among ethanol, the secretory pathway, and dendrite development. The approach is innovative because it introduces a genetically tractable in-vivo system proven to be powerful for molecular and genetic analysis of cell biological problems into ethanol research on cellular organelles. The proposed research is significant because it will fill the gap in our understanding of ethanol effects on the secretory pathway and lead to a mechanistic understanding of ethanol-induced dendrite development. It will also establish an in-vivo system for identifying compounds that block ethanol-induced damage on the secretory pathway and neural development. Thus, it will lay the ground not only for extensive investigation of the role of ethanol on cellular organelles, but also for developing therapeutic strategies to cure ethanol-induced developmental defects.

描述（由申请方提供）：神经元树突损伤是乙醇诱导的神经损伤的关键组成部分。然而，乙醇诱导的枝晶缺陷的机制知之甚少。这些机制的知识是必不可少的，如果我们要了解酒精对神经元发育的影响和设计策略，以防止乙醇对发育中的神经元的破坏性影响。我们的长期目标是确定树突和轴突发育的机制，并确定树突和轴突的缺陷如何导致人类疾病。该研究的目的是描述乙醇诱导的枝晶生长缺陷的机制。以往的研究已经证明了分泌途径在树突发育中的重要性。虽然已知乙醇在各种细胞类型中引起ER应激，但其对ER和高尔基体的影响，这对于膜和分泌蛋白的运输和糖基化以及细胞信号传导至关重要，了解得少得多。申请人已经建立了一个独特的系统，该系统在遗传上易于研究果蝇中的神经元分泌途径。核心假设是乙醇诱导的内质网应激导致内质网重组和高尔基体断裂，从而减少树突状细胞的生长。该假设基于申请人实验室的初步发现。这一假设将通过追求两个具体目标进行检验：1）确定乙醇诱导的神经元ER和高尔基体缺陷的机制; 2）确定乙醇诱导的树突生长缺陷的机制。在第一个目标下，申请人实验室已经建立的可行的遗传技术和细胞生物学测定将被应用于描绘ER应激和相关的细胞因子的作用。乙醇诱导的ER和高尔基体缺陷的反应。在第二个目标下，申请人将利用他在分析枝晶发育方面的专业知识来阐明ER应激和高尔基体断裂在乙醇诱导的枝晶生长中的作用。拟议的研究结果预计将确定乙醇，分泌途径和树突发育之间的因果关系。这种方法是创新的，因为它引入了一个遗传上易于处理的体内系统，该系统被证明是强大的细胞生物学问题的分子和遗传分析到细胞器上的乙醇研究。这项研究意义重大，因为它将填补我们对乙醇对分泌途径影响的理解中的差距，并导致对乙醇诱导的树突发育的机制的理解。它还将建立一个体内系统，用于识别阻断乙醇诱导的分泌途径和神经发育损伤的化合物。因此，它不仅为广泛研究乙醇对细胞器的作用奠定了基础，而且还为开发治疗乙醇诱导的发育缺陷的治疗策略奠定了基础。