Imaging Genetics in Tobacco Smokers

描述(由申请人提供)：这份K02申请为我的职业发展提供了必要的支持，我是一名新的独立研究人员，在成瘾和吸烟的脑成像方面。通过NIDA资助的K01，我在烟草吸烟者的大脑成像方面获得了相当多的专业知识，重点是性别差异。我已经证明了相当大的研究效率，这从我越来越多的同行评议的出版物和目前的赠款资金中得到了证明，包括担任两个R01的首席研究员。这一K02奖项对于提供专注的研究时间和促进我成长为一名完全独立的调查员至关重要。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过程中大脑受体的变化，并确定可能调节这些受体变化的生物标记物，从而影响烟草戒烟努力。提案中包含了一份严格的5年职业发展培训计划，填补了重要的空白，补充了我目前在SPECT/PET神经感受器成像方面的专业知识。具体地说，我计划拓宽我在遗传学、认知和功能磁共振三个领域的知识，以便我可以将它们整合到我对烟草吸烟和成瘾的研究中，以便对未来的治疗产生更大的影响。强化培训由综合课程提供，包括校内课程、校外短期课程、三个个别导师、互动座谈会和与研究有关的组织会议。NIDA资助的一项主要研究(R01)考察了基因对习惯性吸烟者和非吸烟者烟碱型乙酰胆碱受体可用性的影响。我们之前已经使用[123I]5-IA-85380和SPECT脑成像证明，在纹状体以及整个大脑皮层和小脑中，含有烟碱型乙酰胆碱受体(β2-nAChRs)的β2亚单位(β2-nAChRs)比不吸烟者高(26-36%)，这些受体需要戒烟6-12次才能恢复到对照水平。后一项研究的结果是不同的，一些受试者在禁欲后表现出高达17%的下降，而另一些受试者表现出微小的变化，例如4%。目前这项研究的目的是确定在急性和长期戒断期间，这种β-nAChR可获得性的个体变异性是否由基因调节。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)确定在从不吸烟的欧美(EA)吸烟者中，Beta2-nAChR的可用性是否由遗传决定，2)确定EA吸烟者中Beta2-nAChR可用性的适应性增加是否由遗传决定，以及3)确定EA吸烟者从目标2戒烟的前6-8周内Beta2-nAChR可用性的变化是否由遗传决定。重点关注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，从而在未来的研究中对吸烟者进行分层和测试对 各种戒烟疗法。 与公共健康相关：吸烟是已知的可预防死亡的主要原因，但25%的美国人口仍在吸烟。烟碱型乙酰胆碱受体(NAChR)是参与吸烟成瘾的重要神经化学底物。这些研究将确定可能导致吸烟个体差异的基因和大脑化学物质，并将有助于设计最终有助于定制戒烟治疗的治疗研究。

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. PUBLIC HEALTH RELEVANCE: Smoking is the leading known cause of preventable death, yet 25% of the American population continues to smoke. The nicotinic acetylcholine receptor (nAChR) is a critical neurochemical substrate involved in the addiction to cigarette smoking. These studies will define the genes and brain chemicals that may contribute to individual differences in tobacco smoking and will help to design treatment studies that will ultimately help tailor smoking cessation treatments.