University of Southern California (USC)

计划目标和范围。在美国，烟草使用是导致过早死亡的首要原因，大约21%的成年人目前是吸烟者，近年来吸烟率没有下降。虽然现有的药物疗法可以帮助戒烟，但戒烟率在吸烟者的亚组中差异很大。因此，吸烟是一个重要的临床问题，非常需要研究以改善治疗结果。尼古丁成瘾治疗药物遗传学（PNAT）研究计划的目标是为希望戒烟的个人提供证据基础，以优化药物选择。在过去4年中，该跨学科团队在药物遗传学（PGx）科学方面建立了坚实的基础。我们在这一竞争性更新中建议：（a）进行多中心前瞻性分层PGx临床试验，以确定遗传信息生物标志物的预测有效性和成本效益，从而优化戒烟治疗;（B）鉴定改变尼古丁药代动力学（PK）的其他基因变体，以及影响治疗反应的药效学（PD）基因变体;以及（c）阐明PGx标志物与戒烟之间联系的因果机制。

Program Goals and Scope. Tobacco use is the foremost cause of premature death in the U.S. About 21% of adults are current smokers and smoking rates have not declined in recent years. Although available pharmacotherapies can aid in quitting smoking, quit rates vary substantially in subgroups of smokers. Thus, smoking is a significant clinical problem with a great need for research to improve treatment outcomes. The goal of the Pharmacogenetics of Nicotine Addiction Treatment (PNAT) research program is to generate the evidence base to optimize pharmacotherapeutic choices for individuals who wish to quit smoking. Building upon a strong foundafion of translafional pharmacogenefic (PGx) science conducted by this transdiscipiinary team during the past 4 vears. we propose in this competing renewal to: (a) conduct a multi-center prospective stratified PGx clinical trial to establish the predictive validity and cost-effectiveness of a genetically-informed biomarker to optimize smoking cessation treatment; (b) identify additional gene variants altering nicotine pharmacokinetics (PK), as well as pharmacodynamic (PD) gene variants influencing therapeutic response; and (c) elucidate causal mechanisms underiying associations of our PGx marker with smoking cessation.