Center on Genetic Determinants of Alcohol Ingestion and Responses to Alcohol

描述（由申请人提供）：印第安纳酒精研究中心的研究人员在开发和鉴定选定的啮齿动物系方面处于世界领先地位，这些啮齿动物系用于研究酒精偏好和渴望，应用酒精钳以允许精确控制血液酒精水平，以及识别和研究影响酒精反应和酒精中毒风险的遗传变异。在下一个支助期间，我们将1)扩大现有的针对世界各地卫生和法律专业人员的酗酒问题教育、合作研究和外联活动；2)继续选育，为中心研究人员提供大鼠（P/NP、HAD/LAD）和小鼠（HAP/LAP）品系；3)为中心研究人员和合作者提供基因组（表达谱，实时PCR确认mrna变化，高密度SNP基因分型/单倍型，ADH和ALDH基因分型）专业知识；4)有酒精家族史的受试者对酒精的反应、额叶功能磁共振成像活动、药代动力学和预测未来酒精中毒风险的因素与GABRA2和ADH4基因座的风险基因型之间的相关性；5)检测酒精暴露模式下P/NP和HAD/LAD大鼠腹侧被盖区和伏隔壳区的mRNA表达谱；6)研究高度酒精偏好与尼古丁和可卡因敏感性之间的关系，以及这些药物对酒精反应的影响；7)研究酒精暴露胚胎中胚胎基因表达的时空模式以及这些变化的相关转录机制；8)支持与本中心主题相关的创新试点项目：脑功能成像、酒精致畸的三维分析、对纳曲酮的反应和嗜酒的遗传学以及斑马鱼的酒精致畸；9)为培养本科生、研究生、博士后和访问科学家提供了丰富的环境。作为一个成熟的中心，我们将继续指导年轻的教师在中心和更广泛的酗酒研究领域发挥领导作用。

DESCRIPTION (provided by applicant): Investigators of the Indiana Alcohol Research Center are world leaders in the development and characterization of selected lines of rodents for studies on alcohol preference and craving, the application of the alcohol clamp to permit precise control of blood alcohol levels, and the identification and study of genetic variants which influence responses to alcohol and risk of alcoholism. In the next period of support, we will 1) expand existing educational, collaborative research, and outreach activities on alcoholism for health and legal professionals around the world; 2) continue selective breeding and provide rat (P/NP, HAD/LAD) and mouse (HAP/LAP) lines for Center investigators; 3) provide genomic (expression profiling, real-time PCR confirmation of changes in mRNAs, high density SNP genotyping /haplotyping, ADH and ALDH genotyping) expertise for Center investigators and collaborators; 4) correlate responses to alcohol, frontal lobe fMRI activity, pharmacokinetics, and factors that predict the risk for future alcoholism in subjects with family history of alcoholism and risk genotypes at the GABRA2 and ADH4 loci; 5) examine mRNA expression profiles in the ventral tegmentum and accumbens-shell regions of P/NP and HAD/LAD rats during alcohol exposure paradigms; 6) examine associations between high alcohol preference and sensitivity to nicotine and cocaine, and the effects of these drugs on alcohol responses; 7) examine spatial and termporal patterns of embryonic gene expression in alcohol-exposed embryos, and relevant transcriptional mechanisms for these changes; 8) support innovative pilot projects linked to the themes of the Center: functional brain imaging, 3 dimensional analysis of alcohol teratogenesis, genetics of response to naltrexone and of craving for alcohol, and alcohol teratogenesis in zebrafish; and 9) provide a rich environment for the training of undergraduate and graduate students, postdoctoral fellows, and visiting scientists. As a well-established Center, we will continue to mentor younger faculty for leadership roles in the Center and in the broader alcoholism research field. Public Health Relevance: These studies will provide better understanding of how genetic backgrounds affect responses to alcohol and other drugs of abuse, explanations for the sensitivity of the developing fetus to alcohol, and will seek to expand knowledge about alcoholism among health professionals and legal authorities, both in the US and around the world.