NICOTINE DEPENDENCE: RISK & RECOVERY OVER GENERATIONS

描述：(申请人描述)本TTURC的总体目标是确定家庭、幼儿和终生精神因素，这些因素决定：从吸烟开始到依赖的进展轨迹；终生吸烟模式；自然戒烟过程；以及对治疗的反应。我们建议的研究方案结合了治疗/预防的必要性、遗传流行病学方法和生命周期发展视角，共享共同的科学资源，将人类尼古丁依赖的研究从基本机制推进到应用干预。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研究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危险因素，这些因素可作为预防目标，并可用于加强吸烟预防和戒烟治疗的成功。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底物协同作用，或与之相反，因此需要环境和遗传/家族相结合的战略，以清楚地确定显著的环境因素，并为易感基因的研究做准备。为此，我们建议：L)将多学科视角和研究方法整合到基础科学的应用中，包括(A)纵向自然史研究(发展流行病学)；(B)家族聚集方法(遗传流行病学)；(C)人体实验室研究；(D)干预试验；(2)采用这种跨代遗传流行病学方法，帮助了解以下情况的风险因素和致因途径：(A)青年尼古丁依赖的进展；(B)成人吸烟的模式；(C)戒烟的自然过程；以及(D)治疗的反应；(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，该方法针对吸烟者的风险状况(从相对简单的到多种并存)，采用随干预强度和方式的维度而变化的一系列治疗选择；(4)收集和保存DNA，预期在完善表型定义、鉴定候选基因(在其他样本中)以及确定最可遗传的吸烟行为形式之后，我们可以告知并实施高效且多产的策略，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.