Research Project
8353330
The Alcohol Center for Translational Genetics (ACTG) will have two major themes. The first will be to study novel proteins to determine whether they or the signaling pathways in which they participate contain potential drug targets for treating alcohol use disorders. The other main theme of the ACTG will be to investigate whether the genes that encode these proteins are associated with risk of alcoholism in humans. The proteins and signaling pathways in which they participate will be chosen from ongoing invertebrate genetic screens or ex vivo and in vitro studies. The approach is based on the intriguing hypothesis that genes identified in these model systems have relevance for human alcoholism. This hypothesis has been validated, in part, by studies demonstrating the importance of PKA- and PKC-mediated signaling, and specific peptides and ion channels in behavioral responses to alcohol in invertebrates, cultured neural cells and rodents. Candidate proteins will be validated in rat and mouse behavioral models that measure either the level of response to acute ethanol exposure or drug self-administration and reward. Allelic variants in humans will be identified that are predicted to alter gene expression or protein function and confer risk of alcoholism in humans. Four research components, four core components, and a pilot project component address these themes. Three research projects will focus on intensively studying genes novel to the alcohol research community in mice and rats: H-Ras (Component 5), munc-79 (Component 6), and Tao kinases (Component 7). A fourth research project (Component 8) will identify variants of these and related genes in humans and, perform studies to examine their functional significance. In addition to an Administrative Core (Component 1) to manage ACTG functions, there will be three Scientific Cores. An Animal and Behavior Core (Component 2) will establish a standardized battery of behavioral studies for all research projects using mice, and will provide mouse breeding and genotyping services and assistance with complex behavioral studies for the ACTG. A Transgenic and Imaging Core (Component 3) will provide state-of-the art services for generating gene-targeted mice and viral vectors for expression of transgenes or gene silencing by RNA interference in rats and mice. A Genomics core (Component 4) will provide high-throughput sequencing capability, bioinformatics tools and support, and assistance with quantitative RT-PCR. Two Pilot projects will perform early studies of novel proteins and pathways involving atypical protein kinase C isozymes in rats, a Drosophila MAP kinase phosphatase, and a Drosophila BMP2/4 homolog. Collectively, the ACTG will provide a unique center for the detailed study across species of novel genes that may lead to the development of new approaches for preventing and treating alcohol use disorders in humans.
