Psychobiological /Genetic Determinants-Smoking Cessation

描述(由申请人提供)： 我的职业目标是发展经验、技能和基础设施，成为戒烟研究的独立研究员，重点是分子遗传学。这份K08指导临床科学家奖提案概述了与赞助商雷蒙德·尼奥拉(Raymond Niaura)(布朗大学的博士)和共同赞助人(乔治敦大学(Georgetown University)医学博士彼得·希尔兹(Peter Shields))共同发起的为期五年的药物遗传学戒烟临床试验监督研究的综合计划，与布朗大学跨学科烟草使用研究中心整合的结构化教学研讨会系列，以及乔治敦大学(Georgetown University)基因分型技术的实验室培训，以及在布朗大学建立独立实验室。这项工作将由牛津大学一个杰出的跨学科导师网络和与共同赞助者的合作研究提供信息。建议的研究重点是评估多巴胺转运体SLC6A3和其他多巴胺能候选基因多态在吸烟者对盐酸安非他酮戒烟治疗反应中的作用。这项拟议的研究将是第一项探索基因和治疗如何通过多种认知、行为、情感和生理内表型相互作用来减少吸烟的强化特性并影响吸烟结果的研究。 具体目标是： (1)探讨多巴胺转运体SLC6A3基因多态性在安非他酮戒烟治疗反应中的作用。 (2)检验以下假设：安非他酮降低吸烟的增强特性，并且在携带DRD2-Taq1A2/A2基因的吸烟者中，安非他酮降低吸烟增强特性的效果将显著大于携带DRD2-Taq1A1/A1或A1/A2基因的吸烟者， (3)探讨DRD2-Taq1A2/A2和DRD2-Taq1A1/A1或A1/A2等位基因在吸烟者中与线索反应性之间的交互作用。 (4)探讨多巴胺能候选基因多态性对安非他酮戒烟疗效及多种内表型的影响。

DESCRIPTION (provided by applicant): My career goal is to develop the experience, skills, and infrastructure to become an independent investigator in smoking cessation research with a focus on molecular genetics. This K08 Mentored Clinical Scientist Award proposal outlines a comprehensive, five-year program of supervised research in pharmacogenetic smoking cessation clinical trials with Sponsors Raymond Niaura, Ph.D. at Brown University, and Co-Sponsor Peter Shields, M.D. at Georgetown University, a structured didactic seminar series integrated with the Transdisciplinary Tobacco Use Research Center at Brown University combined with laboratory training in genotyping techniques at Georgetown University and establishment of an independent laboratory at Brown University. This work will be informed by an outstanding network of transdisciplinary mentors and collaborative research with Co-Sponsors at the University of Oxford. The focus of the proposed research is an evaluation of the role of the dopamine transporter SLC6A3 polymorphism, and other dopaminergic candidate gene polymorphisms, in treatment response of smokers to bupropion hydrochloride for smoking cessation. The proposed research would be the first study to explore how genotype and treatment interact through multiple cognitive, behavioral, affective, and physiological endophenotypes to reduce the reinforcing properties of smoking and impact smoking outcomes. The specific aims are: (1) To evaluate the role of the dopamine transporter SLC6A3 polymorphism in treatment response to bupropion for smoking cessation, (2) To test the hypotheses that bupropion diminishes the reinforcing properties of smoking and that the effect of bupropion on reduction of the reinforcing properties of smoking will be significantly greater among smokers who carry DRD2-Taq1 A2/A2 genotypes than it is among smokers with DRD2-Taq1 A1/A1 or A1/A2 genotypes, (3) To investigate the interaction between genotype and cue reactivity among smokers with DRD2-Taq1 A2/A2 and DRD2-Taq1 A1/A1 or A1/A2 genotypes, and (4) To evaluate the impact of additional dopaminergic candidate gene polymorphisms on treatment response to bupropion for smoking cessation and multiple endophenotypes.