Alcohol addiction is a complex disease that alters molecular pathways within the brain and leads to the development of alcohol tolerance. One of alcohol's primary targets in the brain is BK potassium channels. BK channels are alternatively spliced and the splice variant expression is regulated by miR-9. Exposure to alcohol upregulates miR-9, an miRNA that modifies the cellular composition of BK channel isoforms and contributes to alcohol tolerance. The molecular mechanisms by which miR-9 is upregulated upon alcohol exposure are currently unknown. We hypothesize that miR-9 upregulation occurs at the transcriptional and/or post-transcriptional level and that inhibition of miR-9 will diminish the acute and long-term effects of alcoholism. We will investigate whether alcohol upregulates miR-9 through interactions with the miR-9 promoter and attempt to identify alcohol sensitive regions of the miR-9 promoter. Another mechanism by which alcohol may upregulate miR-9 is by directing post-transcriptional miRNA maturation through interactions with the enzymes Drosha or Dicer. Lastly, we will inhibit miR-9 expression through RNAi to characterize its role in ethanol sensitivity. Identification of the mechanism underlying miR-9 upregulation after exposure to alcohol will not only provide further insight into alcohol addiction, but may also contribute to the development of potential therapeutic treatments for alcoholism.
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