Genetic Determinants of Drug Effects

描述(由申请人提供)： 项目摘要/摘要酒精和尼古丁的使用可能是对压力和负性生活事件的反应，但也可能受到遗传因素的影响。一个遗传风险因素是对酒精和尼古丁的敏感性，包括对更积极的刺激效应和可能限制摄入量的抑制效应的敏感性。我们已经确定了包含影响尼古丁和酒精敏感性的基因的基因区域，并发现这些区域中有一些重叠，这些区域影响对这些高度联合滥用药物的敏感性。这些区域与似乎控制饮酒的基因区域也有一些重叠。药物敏感性的差异(例如，对负面效应的敏感度降低或对正面效应的敏感度增加)可能为进一步的药物试验奠定基础，导致行为和生理变化，影响过度使用是否发展和维持。我们以前的结果表明，胆碱能过程(尼古丁和毒碱)在决定对酒精的敏感性方面很重要，而且酒精和尼古丁敏感性的遗传差异是遗传相关的。目前的工作将建立在我们以前的遗传学和药理学研究的基础上，并将通过检查每种药物特有的基因表达模式以及共同的基因表达模式，进一步探索尼古丁/乙醇的相互作用。将解决的关键问题是：1.尼古丁胆碱能因子是否与酒精敏感性有关，这是问题酒精使用的危险因素？2.毒碱胆碱能因子与酒精敏感性有关吗？3.是否有共同的遗传因素影响对酒精、尼古丁的敏感性以及它们的联合作用？我们将通过使用遗传小鼠模型、基因表达方法、激光切割技术和RNA干扰(RNAi)方法来实现选择性基因沉默。我们有三个具体目标(SO)。SO1将完成小鼠9号染色体上乙醇刺激QTL的小片段同源定位，并推进我们对特定烟碱型乙酰胆碱受体亚单位基因参与的检查。SO2将完成小鼠2号染色体上乙醇刺激QTL的小片段同源定位，并推进我们对M胆碱受体亚型基因和酒精敏感性的研究。SO3将探索共同基因影响尼古丁和乙醇敏感性的可能性，以及对尼古丁和乙醇联合给药的反应。这些研究将结合行为和遗传分析。这里将应用的一些遗传方法将专注于定位于乙醇和/或尼古丁敏感性的QTL区域的特定基因，而其他方法将着眼于更全球的视野，并有可能识别意外的遗传介体。 公共卫生相关性： 项目说明：拟议研究与退伍军人健康和/或医疗保健问题的相关性退伍军人健康和/或医疗保健问题在退伍军人管理局患者群体中普遍存在，退伍军人管理局在物质滥用研究方面的领导地位是众所周知的。药物和酒精滥用影响着各个年龄段和各个时代的退伍军人。对这一问题的关注需要VHA资源的持续投入，以指导药物滥用治疗计划，以解决药物滥用对其他慢性健康问题的复杂影响，如丙型肝炎、艾滋病毒/艾滋病、癌症和心脏病。2006财年，在退伍军人管理局保健机构就诊的355,000名退伍军人被诊断为尼古丁依赖以外的物质使用(质量提高研究倡议[QUERI]物质使用障碍情况说明书，2008年5月；www.hsrd.research.va.gov/QUERI)。越战时期男性退伍军人报告的最常见的精神障碍包括酗酒和/或依赖(54%的终生)和尼古丁依赖(48%的终生)。物质滥用，包括酒精使用障碍，在退伍军人医疗保健系统中排在前三位的诊断(退伍军人事务部研究动态，2007年1月)。从伊拉克战争归来的士兵经常报告酒精问题[110]。老鼠和人类之间在连锁和序列水平上的遗传相似性确保了我们识别的对成瘾相关特征重要的基因可以被识别出来，并检查其在人类对酒精和尼古丁的敏感性和滥用中的作用。此外，我们的研究很可能提出可以在退伍军人管理局和其他临床人群中进行翻译研究的机制。

DESCRIPTION (provided by applicant): Project Summary / Abstract Problematic alcohol and nicotine use may arise in response to stress and negative life events, but may also be influenced by genetic factors. One genetic risk factor is sensitivity to alcohol and nicotine, including sensitivity to the more positive, stimulant effects and to depressant effects that may curb intake. We have identified genetic regions harboring genes that influence sensitivity to nicotine and alcohol, and find some overlap in those regions that influence sensitivity to these highly co-abused drugs. There is also some overlap of these regions with genetic regions that appear to control alcohol consumption. Differences in drug sensitivity (e.g., decreased sensitivity to negative effects or increased sensitivity to positive effects) may lay a foundation for further drug experimentation, leading to behavioral and physiological changes that influence whether excessive use develops and is maintained. Our previous results indicate that cholinergic processes (both nicotinic and muscarinic) are important in determining sensitivity to alcohol, and that genetically-determined differences in alcohol and nicotine sensitivity are genetically correlated. The current work will build on our previous genetic and pharmacological investigations and will additionally explore nicotine/ethanol interactions by examining patterns of gene expression that are specific for each drug, as well as those that are shared in common. The key questions that will be addressed are: 1. Are nicotinic cholinergic factors associated with alcohol sensitivity, a risk factor for problem alcohol use? 2. Are muscarinic cholinergic factors associated with alcohol sensitivity? 3. Are there common genetic factors that influence sensitivity to alcohol, nicotine, and their combined effects? We will advance our explorations through the use of genetic mouse models, gene expression methods, laser dissection technology, and RNA interference (RNAi) methods for selective gene silencing. We have three specific objectives (SO). SO1 will complete small segment congenic mapping of a QTL for ethanol stimulation on mouse chromosome 9, and advance our examination of the involvement of specific nicotinic acetylcholine receptor subunit genes. SO2 will complete small segment congenic mapping of a QTL for ethanol stimulation on mouse chromosome 2, and advance our examination of specific muscarinic acetylcholine receptor subtype genes and alcohol sensitivity. SO3 will explore the possibility that common genes influence nicotine and ethanol sensitivity, as well as the response to nicotine and ethanol co-administration. These studies will combine behavioral and genetic analyses. Some of the genetic methods to be applied here will be focused on specific genes in QTL regions mapped to ethanol and/or nicotine sensitivity, and others will take a more global look and have the potential for identifying unexpected genetic mediators. PUBLIC HEALTH RELEVANCE: Project Narrative: Relevance of the Proposed Research to Veterans Heath and/or Healthcare Issues Problems with alcohol and nicotine use are prevalent in VA patient populations, and the VA's leadership in substance abuse research is well known. Substance and alcohol abuse affect veterans of all ages and eras. Attention to this problem requires a significant ongoing commitment of VHA resources to direct substance abuse treatment programs that address the complicating effects of substance abuse on other chronic health problems such as hepatitis C, HIV/AIDS, cancers, and heart disease. In FY06, 355,000 veterans who presented at VA health facilities had substance use diagnoses other than nicotine dependence (Quality Enhancement Research Initiative [QUERI] Substance Use Disorders Fact Sheet, May 2008; www.hsrd.research.va.gov/queri). The most prevalent psychiatric disorders reported by male vietnam war era veterans [1] include alcohol abuse and/or dependence (54% lifetime) and nicotine dependence (48% lifetime). Substance abuse, including alcohol use disorders, ranks in the top three diagnoses in the VA healthcare system (VA Research Currents, January 2007). Soldiers returning from the Iraq War frequently report alcohol concerns [110]. Genetic similarity at the level of linkage and sequence between the mouse and human ensures that the genes we identify to be of importance to addiction-related traits can be identified and examined for a role in human alcohol and nicotine sensitivity and abuse. Further, our investigations are likely to render mechanisms that can be translationally studied in VA and other clinical populations.