Excessive consumption of alcohol is known to have toxic effects on the fetal, adult and aging nervous system. It is well established that cerebellar neurons are subject to the damaging effects of alcohol administration throughout development. Because the major function of the cerebellum is to modulate movement and balance by integrating sensory input and motor output, any injury to component neurons is likely to lead to the impairment of motor co-ordination. It is plausible that alcohol-induced cerebellar damage is the result of cumulative changes in the expression of many genes. To date, only a fraction of the genes comprising the human and mouse genomes have been assayed for alcohol-induced changes, either individually or by DNA microarrays. Because DNA microarray technology is a 'closed' system, capable of detecting only known genes, we propose to conduct a global analysis of gene expression in the alcohol-exposed mouse cerebellum using Serial Analysis of Gene Expression (SAGE). SAGE is an 'open' system capable of detecting and digitally quantifying both known and, as yet, unknown genes. The proposed experiments involve the construction, sequencing and bioinformatic analysis of routine cerebellar SAGE libraries during the early postnatal period, adulthood and senescence, shortly after exposure to """"""""binge"""""""" amounts of alcohol. The resulting comprehensive and quantitative SAGE database of alcohol-induced changes in gene expression, which includes that of novel genes, will be disseminated via the NCBI website. Future long-term experiments, beyond the scope of this R03 and proposed as part of a planned R01 submission, will be aimed at (1) construction of """"""""timed"""""""" cerebellar SAGE libraries at several time intervals after alcohol exposure; (2) preparation of cerebellar SAGE libraries from mice chronically exposed to alcohol; (3) the full characterization of novel cerebellar genes whose expression is substantially altered as a result of alcohol administration, and (4) the examination of experimental strategies aimed at reversing the toxic effects of alcohol ingestion on cerebellar neurons.
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