Salivary Biomarkers (DNA, RNA and Cortisol), Life Stress and Nicotine Dependence

唾液生物标志物（DNA、RNA 和皮质醇）、生活压力和尼古丁依赖

• 批准号: 7941751
• 负责人: Judy A Andrews
• 金额: $ 88.63万
• 依托单位: OREGON RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7941751
• 关键词: Address; Adolescence; Age; Alcohol or Other Drugs use; Anxiety Disorders; Area; Arts; Biological Markers; Candidate Disease Gene; Caring; Catechol O-Methyltransferase; Childhood; Chronic; Chronic stress; Clinical; Clinical assessments; Collection; Corticotropin-Releasing Hormone Receptors; DNA; DRD2 gene; Data; Depressive disorder; Development; Diagnostic; Disease; Environment; Etiology; Event; Exposure to; Failure; Foundations; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Polymorphism; Goals; Hydrocortisone; Individual; Intervention; Intervention Studies; Interview; Laboratories; Life; Life Stress; Link; Longitudinal Studies; Lymphocyte; Measurement; Measures; Methyltransferase Gene; Moods; National Institute of Drug Abuse; Nicotine; Nicotine Dependence; Noise; Opioid Receptor; Parents; Participant; Pathway interactions; Preventive Intervention; Promoter Regions; Protein Kinase; Questionnaires; RNA; Receptor Gene; Recovery; Research; Research Infrastructure; Research Project Grants; Respondent; Rewards; Saliva; Salivary; Sampling; Schedule; Signal Transduction; Source; Specific qualifier value; Stress; Structure; Substance Use Disorder; Tobacco use; Translational Research; Trier Social Stress Test; United States National Institutes of Health; Validation; Youth; base; cohort; drug abuse prevention; emerging adult; emerging adulthood; experience; functional genomics; genome-wide; improved; novel; prevent; public health relevance; response; serotonin transporter; stressor; success; therapy design; tool

DESCRIPTION (provided by applicant): The broad goal of this project is to lay the foundation for research identifying salivary biomarkers that are predictive of the vulnerability of individuals to (a) progress toward nicotine dependence and (b) ultimately to become dependent on nicotine by emerging adulthood, given their exposure to life stress. Features of the proposed research is the use of an interview-based life stress assessment to provide a precise and reliable measurement of chronic and episodic stress, and initial steps in the identification of easily obtained salivary biomarkers that identify individuals who are exposed to greater levels of chronic stress. This project has the potential to advance drug abuse prevention and intervention research through identifying Genetic x Environment (GxE) interactions, which may help to explain the success or failure of interventions designed to prevent the initiation of tobacco use and the progression to nicotine dependence, or to maintain cessation. The proposed assessment with two cohorts at age 20/21 (n = 390) includes saliva collection for DNA extraction to assess polymorphisms of candidate genes known to be related to the stress-reward pathway, saliva collection for RNA extraction for candidate gene and genome wide gene expression, and a systematic contextual based assessment of chronic and episodic stress, using state-of-the-art assessment tools, at age 20/21. The data from this assessment will be integrated with other multi-source/multi-respondent data from two cohorts from an ongoing eleven-year longitudinal study examining the etiology of substance use, including nicotine dependence, combined with data assessing cortisol reactivity in response to laboratory induced stress, at age 20/21. To accomplish this broad goal, we propose to address the following aims: (1) Identify GxE interactions which predict change in nicotine dependence across from adolescence to emerging adulthood and across youth from the occurrence of polymorphisms of specified candidate gene known to be related to the stress reward pathway in the context of the experience of chronic and episodic stress; (2) Assess the association between specific genetic polymorphisms and cortisol reactivity in response to a laboratory induced stressor and assess the effect of GxE interactions on cortisol dysregulation through examining the effect of the interaction of genetic polymorphisms and life stress in emerging adulthood on cortisol dysregulation; and (3) Evaluate whether the salivary transcriptome contains RNA biomarkers for the identification of individuals with the gene expression signature of chronic stress using RNA samples from 24 individuals who experience the most life stress and 24 individuals with the least stress. We plan to validate an existing functional genomic signature of chronic stress previously identified in lymphocytes by performing gene expression analysis of individual candidate genes, and we will discover, confirm and validate novel candidate genes by performing genome-wide and candidate gene expression analysis. PUBLIC HEALTH RELEVANCE: This project has the potential to advance drug abuse prevention and intervention research through identifying Genetic x Environment (GxE) interactions, which may help to explain the success or failure of interventions designed to prevent the initiation of tobacco use and the progression to nicotine dependence, or to maintain cessation. Results may guide the selection of tailored interventions for specific individuals.

描述（由申请人提供）：本项目的总体目标是为研究确定唾液生物标志物奠定基础，这些生物标志物可预测个体对(a)尼古丁依赖的进展和(b)在成年初期，由于他们暴露于生活压力下，最终对尼古丁依赖的脆弱性。该研究的特点是使用基于访谈的生活压力评估，为慢性和偶发性压力提供精确可靠的测量，并在识别容易获得的唾液生物标志物方面迈出了初步步骤，这些生物标志物可识别暴露于更高水平慢性压力的个体。该项目有可能通过确定遗传x环境（GxE）相互作用来推进药物滥用预防和干预研究，这可能有助于解释旨在防止开始使用烟草和发展为尼古丁依赖或维持戒烟的干预措施的成功或失败。在20/21岁的两个队列（n = 390）中，建议的评估包括唾液收集用于DNA提取以评估已知与应激-奖励途径相关的候选基因的多态性，唾液收集用于RNA提取以评估候选基因和全基因组基因表达，以及使用最先进的评估工具对20/21岁的慢性和间歇性应激进行系统的基于上下文的评估。该评估的数据将与来自两个队列的其他多来源/多应答数据整合，这些数据来自一项正在进行的为期11年的纵向研究，该研究旨在检查物质使用的病因，包括尼古丁依赖，并结合评估20/21岁时实验室诱导压力下皮质醇反应性的数据。为了实现这一广泛的目标，我们建议解决以下目标：(1)确定GxE相互作用，这些相互作用可以预测在慢性和偶发性应激经历中与应激奖励途径相关的特定候选基因多态性的发生，从而预测从青春期到成年初期和青年时期尼古丁依赖性的变化；(2)评估特定遗传多态性与实验室诱导应激源皮质醇反应性之间的关系，并通过研究遗传多态性与生活压力对初成年期皮质醇失调的相互作用，评估GxE相互作用对皮质醇失调的影响；(3)利用24例生活压力最大的个体和24例生活压力最小的个体的RNA样本，评估唾液转录组中是否含有用于识别具有慢性应激基因表达特征个体的RNA生物标志物。我们计划通过对单个候选基因的基因表达分析来验证先前在淋巴细胞中发现的慢性应激的现有功能基因组特征，我们将通过全基因组和候选基因表达分析来发现、确认和验证新的候选基因。公共卫生相关性：该项目有可能通过确定遗传x环境（GxE）相互作用来推进药物滥用预防和干预研究，这可能有助于解释旨在防止开始使用烟草和发展为尼古丁依赖或维持戒烟的干预措施的成功或失败。研究结果可以指导为特定个体选择量身定制的干预措施。