Control of Alcohol Responses by Actin-Regulating Genes

点击翻译按钮获取中文摘要

–––– PROJECT SUMMARY / ABSTRACT FOR THE DIVERSITY SUPPLEMENT ––––––––––––––––––––––––––––– Alcohol abuse disorders (AUD) are a major health hazard that affects millions of people every year in the United States. Risk factors for AUD include initial resistance to the intoxicating effects of alcohol, as well as the development of tolerance upon repeat exposure. AUDs also have significant genetic etiology, and many genes have been implicated from human genome-wide association studies (GWAS), including by our studies. A detailed molecular understanding of many of these genes is still lacking, though. “Regulation of the actin cytoskeleton” has been implicated by numerous mammalian alcohol transcriptomics studies, and major regulators of actin dynamics include the Rho family of GTPases, and their regulators. Our findings, supported by prior funding periods of this competitive renewal grant, have shown that SNPs in the Rho GTPase regulator RSU1 are associated with alcohol dependence and drinking, underscoring the translational significance of our studies. There are several goals to this supplement application: i) in 2 scientific Aims, Pearl Cummins will determine the role of the Rac1 GTPase regulator RhoGAP18B in ethanol-induced tolerance and investigate the neurotransmitter systems that required RhoGAP18B for normal alcohol responses. In a second Aim, Pearl will determine whether Drosophila can be established as a model organism to investigate the mechanisms of hedonic tolerance. The first Aim builds on Aim1 of the parent grant and incorporates some recently generated preliminary data. The parent grant has a focus on alcohol-induced tolerance to the sedating effects of ethanol, as measured by a loss-of-righting assay. Since hedonic tolerance, rather than the tolerance to the motor- incapacitating effects of alcohol, contributes to the escalation of continued alcohol intake, we need to establish whether Drosophila can be used as a high-throughput organism to test the genetic contribution to hedonic tolerance. Thus, Pearl's second Aim is completely novel and innovative, but logically extends from the overarching question of the parent grant. ii) provide Pearl, who has a background in working with human subjects during her prior research, with scientific training on genetic, molecular, and behavioral approaches in model organisms. iii) Mentor Pearl in skills that are conducive to her career development as an independent scientist; For latter two goals, we have developed a detailed plan for Pearl in what the experimental techniques are she will learn and what curricular activities will expand her scientific and career skill development. Regular meeting with the primary mentor, as well as her scientifically diverse mentoring team will provide a trove of expertise to draw from, as well as ensure progress in Pearls scientific development; iv) enrich the workforce by integrating Pearl, who comes from an underprivileged low-income background with no parents holding a Bachelor's degree, in the scientific community here at the University of Utah, as well as the wider addition community.