NICOTINE DEPENDENCE--RISK & RECOVERY OVER GENERATIONS

描述：（申请人描述）本TTURC的总体目标是确定家族性、幼儿期和终生精神病学因素，这些因素决定：从吸烟开始到依赖的发展轨迹；终生吸烟模式；停止：停止的自然过程；以及对治疗的反应。我们提出的研究项目结合了治疗/预防的必要性，遗传流行病学方法和生命发育的观点，共享共同的科学资源，以推进人类尼古丁依赖的研究从基本机制到应用干预。我们将使用基于社区的样本、前瞻性设计和多代家庭研究的协同组合来检查尼古丁依赖的主要途径，并开发和验证烟草使用和尼古丁依赖表型的寿命分类。主要目标是确定可改变的风险因素，这些因素可作为预防目标，并可用于加强预防吸烟和戒烟治疗的成功。我们认识到，许多这种可改变的风险因素可能与遗传风险的基础一致或相反，并认为需要结合环境和遗传/家族策略来明确识别突出的环境因素并为易感基因的研究做好准备。为此，我们建议：1)将基础科学前沿的多学科视角和研究方法整合到应用中，包括：(a)纵向自然史研究（发展流行病学）；(b)家族聚集法（遗传流行病学）；(c)人体实验室研究；(d)干预试验；(2)采用这种寿命和跨代遗传流行病学方法来帮助理解以下因素的风险因素和因果途径：(a)青少年尼古丁依赖的进展；(b)成人吸烟模式；(c)戒烟的自然过程；(d)治疗反应；(3)记录持续的“护理管理”方法治疗吸烟者的潜在效用和成本效益，该方法通过一系列治疗方案，根据干预的强度和方式的不同，解决吸烟者的风险概况（从相对简单到多种合并症）；(4)收集和保存DNA，期望在精炼表型定义，表征候选基因（在其他样本中），并确定最可遗传的吸烟行为形式后，我们可以告知并实施有效和富有成效的策略，以确定尼古丁依赖的易感基因。

DESCRIPTION: (Applicant's Description) The overall aim of this TTURC is to identify familial, early childhood and lifetime psychiatric factors that determine: trajectories of progression from smoking initiation to dependence; lifetime smoking patterns; the natural course of cessation; and response to treatment. Our proposed program of research combines a treatment/prevention imperative, a genetic epidemiologic approach, and a lifespan developmental perspective, sharing common scientific resources, to advance research on human nicotine dependence from basic mechanisms to applied interventions. We will use a synergistic combination of a community-based sample, prospective design, and a multigenerational family study to examine the major pathways to nicotine dependence, and to develop and validate a lifespan taxonomy of tobacco use and nicotine dependence phenotypes. The major goal is to identify modifiable risk factors that can serve as targets for prevention and that may be harnessed to enhance smoking prevention and cessation treatment success. We recognize that many such modifiable risk factors may act in concert with or against a substrate of genetic risks, and reason that a combined environmental and genetic/familial strategy is required both to clearly identify salient environmental agents and to prepare for studies of susceptibility genes. To this end, we propose to: l) To integrate multiple disciplinary perspectives and research methods front basic science to applications including (a) longitudinal natural history research (developmental epidemiology); (b) familial aggregation methods (genetic epidemiology); (c) human laboratory studies; and (d) intervention trials; (2) To adopt this lifespan and transgenerational genetic epidemiological approach to help understand risk factors for and causal pathways of: (a) progression of nicotine dependence among youth; (b) patterns of adult smoking; (c) the natural course of smoking cessation; and (d) response to treatment; (3) To document the potential utility and cost-effectiveness of a sustained "care management" approach to treating smokers that addresses smokers' risk profiles (from relatively uncomplicated to multiple comorbidities) with a range of treatment options that vary along dimensions of intensity and modality of intervention; (4) To collect and preserve DNA with the anticipation that, after refining phenotypic definitions, characterizing candidate genes (in other samples), and identifying the most heritable forms of smoking behavior, we may inform and conduct an efficient and productive strategy to identify susceptibility genes for nicotine dependence.