Imaging Genetics in Tobacco Smokers

描述（由申请人提供）：这份K02申请为我作为一名新近独立的成瘾和吸烟脑成像研究人员的职业发展提供了必要的支持。通过NIDA资助的K01项目，我在吸烟者的脑成像方面获得了相当多的专业知识，重点是性别差异。我已经展示了相当高的研究效率，这可以从我越来越多的同行评审出版物和目前的资助资金中得到证明，包括担任两项r01的首席研究员。这个K02奖对于提供专注的研究时间和促进我成长为一个完全独立的研究者至关重要。我目前的职业目标是使用SPECT和PET成像来检查急性和长期戒烟期间脑受体的变化，并确定可能调节这些受体变化从而影响戒烟努力的生物标志物。提案中包括一个严格的5年职业发展培训计划，填补了重要的空白，并补充了我目前在SPECT/PET神经受体成像方面的专业知识。具体来说，我计划在遗传学、认知学和fMRI这三个领域拓宽我的知识面，将它们整合到我对吸烟和成瘾的研究中，以便对未来的治疗产生更大的影响。强化培训由校内课程、校外短期课程、三个个性化指导、互动式专题讨论会和与研究相关的组织会议的综合课程提供。一项主要的NIDA资助的研究（R01）被纳入其中，该研究检查了遗传对习惯性吸烟者和非吸烟者烟碱乙酰胆碱受体可用性的影响。我们先前使用[123I]5-IA-85380和SPECT脑成像证明，吸烟者与不吸烟者相比，纹状体中含有尼古丁乙酰胆碱受体（β 2- nachrs）的β 2亚基（β 2- nachrs）更高（26-36%），并且在整个大脑皮层和小脑中，这些受体需要戒烟6-12年才能恢复到控制水平。后一项研究的结果是异质的，一些受试者在禁欲后表现出高达17%的下降，而另一些则表现出最小的变化，例如4%。当前研究的目的是确定急性和长期戒断期间β - nachr可用性的个体差异是否由遗传介导。在目前的提案中，我们旨在通过以下具体目标来验证这一假设：1)确定欧洲-美国（EA）从不吸烟者中β 2- nachr可用性是否由遗传决定；2)确定EA吸烟者中β 2- nachr可用性的适应性增加是否由遗传决定；3)确定EA吸烟者戒烟后6-8周内β 2- nachr可用性的变化是否由遗传决定。重点是与尼古丁依赖相关的两个基因，CHRNA4和ANKK1。这些研究的发现可能会提供明确的遗传和神经化学证据，这将允许在未来的研究中对吸烟者进行分层和测试

DESCRIPTION (provided by applicant): This K02 application proposes support essential for my career development as a newly independent researcher in brain imaging of addiction and tobacco smoking. Through a K01 funded by NIDA, I attained considerable expertise in brain imaging of tobacco smokers, with a focus on sex differences. I have demonstrated considerable research productivity as evidenced by my increasing number of peer reviewed publications and current grant funding including being principal investigator on two R01s. This K02 award is vital for providing focused research time and for facilitating my maturation into a fully-independent investigator. My current career goal is to use SPECT and PET imaging to examine brain receptor changes during acute and prolonged abstinence from tobacco smoking and to determine biomarkers that may modulate these receptor changes and thus impact tobacco smoking cessation efforts. Included in the proposal is a rigorous 5-year career development training plan that fills important gaps and complements my current expertise in SPECT/PET neuroreceptor imaging. Specifically, I plan to broaden my knowledge in the three areas of genetics, cognition and fMRI, so that I can integrate them in my research on tobacco smoking and addiction in order to have a greater impact on future treatment. Intensive training is provided by an integrated curriculum of intramural coursework, extramural short courses, three individualized preceptorships, interactive symposia, and research-related organizational meetings. A primary NIDA funded research study (R01) is included that examines genetic influences on nicotinic acetylcholine receptor availability in habitual tobacco smokers and nonsmokers. We have previously demonstrated using [123I]5-IA-85380 and SPECT brain imaging that beta2-subunit containing nicotinic acetylcholine receptors (beta2-nAChRs) are higher (26-36%) in the striatum, and throughout the cerebral cortex and cerebellum in tobacco smokers versus nonsmokers and that it takes up to 6-12 of abstinence for these receptors to return to control levels. The findings from the latter study were heterogeneous, with some subjects showing decreases of up to 17% over abstinence and others showing minimal change, e.g., 4%. The goal of the current study is to determine whether this individual variability in beta-nAChR availability during acute and prolonged abstinence is genetically mediated. In the present proposal, we aim to validate this hypothesis through the following specific aims: 1) to determine if beta2-nAChR availability is genetically determined in European-American (EA) never smokers, 2) to determine if the adaptive increase in beta2-nAChR availability in EA smokers is genetically determined and 3) to determine if the change in beta2-nAChR availability over the first 6-8 weeks of abstinence in EA smokers from Aim 2 is genetically determined. The focus is on 2 genes that have been associated with nicotine dependence, the CHRNA4 and ANKK1. The findings from these studies may provide definitive genetic and neurochemical evidence that will allow in future studies for smokers to be stratified and tested for responses to various smoking cessation treatments.