Genetics of Alcohol and Nicotine Behaviors

描述（由申请人提供）：酒精和尼古丁是常见的共同滥用物质。遗传学研究提供的证据表明，基因独立地影响对这两种药物的反应，但最近有数据表明，共同基因可能影响对这两种药物的反应。大量的动物实验证明神经元尼古丁乙酰胆碱受体，特别是1422-受体参与了对尼古丁的行为反应。重要的是，这些受体也与对酒精的某些影响的敏感性有关。含有14和22亚基的烟碱乙酰胆碱受体已被证明在调节多巴胺释放中发挥关键作用，而多巴胺释放是对滥用药物的潜在反应的重要大脑区域。本研究的重点是这些受体亚基在酒精和尼古丁行为中自然变异的作用。将使用两个样本来确定编码这些亚基的基因中的单核苷酸多态性（snp）是否影响对酒精和尼古丁表型的敏感性。已经从科罗拉多反社会药物依赖中心（CADD）和国家青年调查（NYS）收集的DNA和表型数据将用于分析。候选人将使用重测序和基于家族的关联测试来检查这些基因的影响。此外，发现与酒精或尼古丁行为相关的snp将使用基于荧光素酶的基因表达测定进行功能表征。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，候选人除了与导师定期会面外，还需要参加课程、专题讨论会、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药物滥用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。这项新的培训将补充候选人之前在小鼠行为遗传学方面的培训，并将对候选人成为一名独立研究人员的长期目标非常重要。通过在人类统计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群体之间的转化问题。

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.