Translational studies of nicotinic receptor genes: alcohol and nicotine behaviors

烟碱受体基因的转化研究：酒精和尼古丁行为

• 批准号: 7921055
• 负责人: MARISSA A EHRINGER
• 金额: $ 58.81万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7921055
• 关键词: 5' Untranslated Regions; Age; Agonist; Alcohol dependence; Alcohol or Other Drugs use; Alcohols; Alleles; Award; Behavior; Behavioral; Behavioral Model; Binding; Biological Assay; Biological Models; Biological Process; Cations; Cell Culture Techniques; Comorbidity; Complex; DNA; DNA Resequencing; Data; Dependence; Development; Disease; Dopamine; Drosophila acetylcholine receptor alpha-subunit; Drug Addiction; Drug effect disorder; Electrophysiology (science); Family; Future; Gated Ion Channel; Gene Expression; Genes; Genetic; Genetic Risk; Genomics; Genotype; Goals; Heritability; Human; Human Genetics; Individual; Intercistronic Region; Knowledge; Laboratories; Lead; Ligands; Malignant neoplasm of lung; Mediating; Mentors; Methods; Molecular; Mus; Neurons; Nicotine; Nicotine Dependence; Nicotinic Receptors; Nucleic Acid Regulatory Sequences; Pathway interactions; Pharmacogenomics; Phenotype; Play; Prevention; Prevention approach; Promoter Regions; Property; Rattus; Receptor Gene; Research; Rewards; Rodent Model; Role; Sampling; Severities; Single Nucleotide Polymorphism; Site; Smoking; Testing; Tobacco; Tobacco use; Training; Variant; Work; Xenopus oocyte; addiction; alcohol response; alcohol use initiation; anti social; base; career; case control; dopaminergic neuron; follow-up; genetic association; genome wide association study; improved; mesolimbic system; novel; problem drinker; public health relevance; receptor; receptor function; response; translational study

DESCRIPTION (provided by applicant): Alcohol and nicotine dependence commonly co-occur and a variety of research suggests some of this co-morbidity may be due to overlapping genetic factors. Converging evidence from electrophysiology studies and rodent models of alcohol- and tobacco-related phenotypes supports the hypothesis that neuronal nicotinic receptors (nAChRs) may be a common site of action for these drugs. The nAChRs are ligand-gated ion channels containing a central cation pore that act as the primary targets for nicotine and the endogenous agonist acytelcholine. Alcohol appears to play a role in modulating the pharmacological properties of nicotine binding at nAChRs, usually by enhancing receptor function. Furthermore, several nicotinic receptor subtypes are known to be present on dopaminergic neurons and involved in mediating the release of dopamine in response to alcohol and nicotine. Through this mesolimbic dopaminergic pathway, these receptors (including the 13-7 and 22-4 subunits) may contribute to the rewarding properties associated with substance use. Recent work has provided evidence that several of the human nAChR subunit genes are associated with alcohol and nicotine behaviors in humans, including age of initiation, early subjective response, and dependence. This proposal will extend these human studies in three ways. First, the human genes for the 13-6 and 22-4 nAChR subunits will be resequenced using DNA samples from 100 individuals to identify novel variations. Second, multiple variations in these genes will be characterized in a sample of 4,146 individuals, for which DNA and alcohol and nicotine behavioral data have already been collected, to test for associations between specific DNA variations and these behaviors. Third, laboratory-based methods will be conducted to determine whether specific variations lead differences in gene expression using cell culture assays. PUBLIC HEALTH RELEVANCE: Results from each of these aims will facilitate a better understanding of how naturally occurring variations in these genes might contribute to the underlying molecular mechanisms responsible for differences in alcohol and nicotine behaviors. Such knowledge should lead to the development of improved prevention and treatment of individuals who suffer from these disorders.

描述（由申请人提供）：酒精和尼古丁依赖通常同时发生，并且各种研究表明这种共病的一些可能是由于重叠的遗传因素造成的。来自电生理学研究和酒精和烟草相关表型的啮齿动物模型的综合证据支持了这样的假设：神经元烟碱受体（nAChR）可能是这些药物的共同作用位点。 nAChR 是配体门控离子通道，含有中央阳离子孔，作为尼古丁和内源激动剂乙酰胆碱的主要靶标。酒精似乎在调节尼古丁与 nAChR 结合的药理学特性方面发挥着作用，通常是通过增强受体功能。此外，已知多种烟碱受体亚型存在于多巴胺能神经元上，并参与介导响应酒精和尼古丁的多巴胺释放。通过这种中脑边缘多巴胺能途径，这些受体（包括 13-7 和 22-4 亚基）可能有助于与物质使用相关的奖励特性。最近的工作提供的证据表明，人类的几个 nAChR 亚基基因与人类的酒精和尼古丁行为有关，包括开始年龄、早期主观反应和依赖。该提案将从三个方面扩展这些人类研究。首先，将使用 100 名个体的 DNA 样本对 13-6 和 22-4 nAChR 亚基的人类基因进行重新测序，以识别新的变异。其次，我们将在 4,146 名个体样本中表征这些基因的多种变异，并已收集了这些样本的 DNA 以及酒精和尼古丁行为数据，以测试特定 DNA 变异与这些行为之间的关联。第三，将采用基于实验室的方法来使用细胞培养测定来确定特定变异是否导致基因表达差异。 公共健康相关性：每个目标的结果将有助于更好地理解这些基因中自然发生的变异如何促成导致酒精和尼古丁行为差异的潜在分子机制。这些知识应该有助于改进对患有这些疾病的个体的预防和治疗。