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

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

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.