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

描述（申请人提供）：神经元树突损伤是乙醇性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尚不清楚。如果我们要了解酒精对神经元发育的影响，并设计防止乙醇对发育中的神经元的破坏性影响的策略，这些机制的知识是必不可少的。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。本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通路在树突发育中的重要性。虽然已知乙醇会引起各种细胞类型的内质网应激，但其对内质网和高尔基体的影响却知之甚少，而内质网和高尔基体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。申请人已经建立了一个独特的系统，是遗传上易于处理的，用于研究果蝇的神经元分泌途径。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断裂，从而减少树突生长。这一假设是基于申请人实验室的初步发现。这一假设将通过以下两个具体目标进行验证：1)确定乙醇诱导神经元内质网和高尔基体缺陷的机制；2)确定乙醇诱导枝晶生长缺陷的机制。在第一个目标下，已经在申请人实验室建立可行的基因技术和细胞生物学分析将被应用于描述内质网应激及其相关的作用

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.