Genetics of Alcohol and Nicotine Behaviors

描述(申请人提供)：酒精和尼古丁是常见的共同滥用物质。遗传学研究已经提供了证据，表明基因独立地影响这两种药物的反应，但最近有数据表明，共同的基因(S)可能影响这两种药物的反应。大量的动物研究表明，神经元烟碱型乙酰胆碱受体，尤其是含1422的受体参与了尼古丁的行为反应。对这一提议很重要的是，这些受体也与酒精的某些影响有关。包含14和22个亚基的烟碱型乙酰胆碱受体已被证明在调节大脑区域的多巴胺释放方面发挥关键作用，这些区域是已知的对滥用药物的潜在反应重要的区域。这项建议侧重于这些受体亚基的自然变异在酒精和尼古丁行为中的作用。两个样本将被用来确定编码这些亚单位的基因中的单核苷酸多态(SNPs)是否会影响对酒精和尼古丁表型的敏感性。已经从科罗拉多州反社会药物依赖中心(CADD)和全国青年调查(NYS)研究中收集的DNA和表型数据将可用于分析。候选人将使用重新测序和基于家庭的关联测试来检查这些基因的影响。此外，被发现与酒精或尼古丁行为相关的SNPs将使用基于荧光素酶的基因表达分析来进行功能表征。通过这个项目，候选人将实现学习人类统计遗传学、分子遗传学和生物信息学工具的短期目标。为了学习这些方法，候选人除了定期与导师会面外，还将参加课程作业、研讨会、研讨会和会议。这个项目的所有导师都是行为遗传学研究所的教员。这种环境是进行这种培训的理想环境，因为研究所在研究与人类滥用药物的遗传学有关的问题以及使用动物和分子方法方面有着悠久的历史。这一新的培训将补充候选人之前在老鼠行为遗传学方面的培训，对于候选人成为一名独立研究人员的长期目标将非常重要。通过在人类统计学和分子遗传学方面的额外培训，候选人希望最终评估模式生物和人类种群之间的翻译问题。

DESCRIPTION (provided by applicant): Alcohol and nicotine are commonly co-abused substances. Genetic studies have provided evidence that genes influence the responses to both of these drugs independently, but more recently there have been data to suggest that common gene(s) are likely to influence responses to both drugs. There is an abundant amount of animal research providing evidence that neuronal nicotinic acetylcholine receptors, in particular 1422- containing receptors are involved in the behavioral responses to nicotine. Important for this proposal, these receptors have also been implicated in sensitivity to some effects of alcohol. Nicotinic acetylcholine receptors containing the 14 and 22 subunits have been shown to play a key role in regulating dopamine release in brain regions known to be important for underlying responses to abused drugs. This proposal focuses on the role of natural variation in these receptor subunits in alcohol and nicotine behaviors. Two samples will be used to determine if single nucleotide polymorphisms (SNPs) in the genes encoding these subunits influence sensitivity to alcohol and nicotine phenotypes. DNA and phenotypic data that have already been collected from the Colorado Center for Antisocial Drug Dependence (CADD) and the National Youth Survey (NYS) studies will be available for analysis. The candidate will examine the influence of these genes using resequencing and family-based association tests. Furthermore, the SNPs found to be associated with alcohol or nicotine behaviors will be functionally characterized using luciferase-based gene expression assays. Through this project the candidate will achieve her short-term goal of learning human statistical genetics, molecular genetics and bioinformatics tools. To learn these methods the candidate will attend coursework, symposia, workshops and conferences, in addition to having regular meeting with her mentors. All mentors of this project are faculty fellows at the Institute for Behavioral Genetics. This environment is ideal for such training because of the Institute's long history in studying questions related to the genetics of substance abuse in humans and using animal and molecular approaches. This new training will complement the candidate's prior training in mouse behavioral genetics and will be important for the candidate's long-term goal of becoming an independent researcher. With this additional training in human statistical and molecular genetics the candidate hopes to ultimately evaluate translational questions between model organism and human populations.