Novel gene pathways hypothesized to be involved in excessive drinking were discovered from extensive gene expression studies using gene arrays in the rodent lines genetically predisposed to drink excessively and by using animal models of excessive drinking. Three major functional gene pathways have been identified. Each brings gene targets unique to the alcohol field. The pathways are in the following areas: neuroinflammation, ion channels, and second messenger systems. Whole-genome analyses of INIA-West gene candidates have been performed in human samples, and Next Generation sequencing is being established at several INIA sites to extend our previous genomic studies.      Novel molecular approaches include the development of a cre recombinase mouse specific for neurons in the extended amygdala. Such a project would not have been possible through the R01 mechanism because it required a sustained effort using gene arrays, sophisticated molecular biology, and knowledge derived from INIA-West collaborations. In addition, electrophysiological assays for the mechanism of action of INIA target genes have been established with a focus on brain sites with brain circuitry identified as critical by INIA-West for excessive alcohol drinking, such as the nucleus accumbens (NAc) and central nucleus of the amygdala (CeA). Brain imaging of excessive drinking models has been successfully implemented, and imaging of molecular targets is planned. The translation potential across flies, mice, rats, monkeys, and humans is being exploited. Capitalizing on these substantial advances, the overall goals of INIA-West are: (1) to identify molecular-genetic targets within the neurocircuitry and neurobiology responsible for excessive alcohol intake and (2) to provide the foundation to enable translation of the basic neuroscience findings to targets for medication development for treating the human clinical condition. The overall INIA-West Specific Aims for the renewal of the consortium are:

Specific Aim 1.      To confirm gene targets nominated by expression assays or other methods by use of transgenic, knockout, inducible knockout, site-specific knockout, RNAi, in situ hybridization, in vivo electrophysiology, in vivo imaging, and next-generation sequencing

Specific Aim 2.      To identify druggable targets that are most promising for medication development for the treatment of alcoholism by use of novel molecules in concert with molecules with existing FDA approval in animal models with the most predictive ability

Specific Aim 3.      To attract new and innovative investigators to the field of alcohol research by recruiting individuals for U01 grants and Pilot projects and by making the informatics integrated datasets accessible, searchable, and interactive with other databases for all scientists interested in alcoholism research.



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