University of Toronto Coordinating Genetics Core & Clinical Trial Site

多伦多大学协调遗传学核心

• 批准号: 8703049
• 负责人: RACHEL Fynvola TYNDALE
• 金额: $ 32.46万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8703049
• 关键词: Accounting; Adult; Adverse effects; Algorithms; Alleles; Alternative Therapies; Biological Markers; Brain; CYP2B6 gene; Candidate Disease Gene; Cessation of life; Cigarette; Clinical; Clinical Trials; DRD2 gene; Data; Dopamine D2 Receptor; Drug Kinetics; Foundations; Genes; Genetic; Genetic Variation; Glucuronosyltransferase; Goals; Half-Life; High Prevalence; Human; Individual; Inherited; Laboratories; Metabolism; Molecular Target; Nausea; Nicotine; Nicotine Dependence; Nicotine Withdrawal; Nicotinic Receptors; Patient Self-Report; Pharmacodynamics; Pharmacogenetics; Pharmacotherapy; Placebos; Randomized; Relapse; Reporting; Research; Rewards; Risk; Science; Severities; Site; Smoke; Smoker; Smoking; Source; Subgroup; Symptoms; Techniques; Testing; Therapeutic; Time; Tobacco use; Treatment outcome; Universities; Variant; Withdrawal Symptom; Withholding Treatment; arm; base; cohort; cost; cost effective; cost effectiveness; craving; cytochrome P-450 CYP2A6 (human); deprivation; evidence base; experience; genetic variant; improved; meetings; novel; premature; programs; prospective; research study; response; simulation; smoking cessation; varenicline

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 foundation of translational pharmacogenetic (PGx) science conducted by this transdisciplinary team during the past 4 years. 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 underlying associations of our PGx marker with smoking cessation.

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，吸烟是一个重大的临床问题，迫切需要进行研究以改善治疗效果。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。建立在这个跨学科团队在过去4年中进行的转化药物遗传学（PGx）科学的坚实基础上。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;和（c）阐明我们的PGx标记物与戒烟相关的因果机制。