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A multilevel vulnerability study of substance abuse via CNV, brain activation and

通过 CNV、大脑激活和药物滥用的多层次脆弱性研究

基本信息

批准号：
8322142
负责人：
Jingyu Liu
金额：
$ 33.66万
依托单位：
THE MIND RESEARCH NETWORK
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8322142
关键词：
Affect Alcohol abuse Alcohol dependence Alcohols Base Sequence Behavior Behavior assessment Behavioral Biology Brain Brain region Comorbidity Copy Number Polymorphism DNA Data Development Diagnosis Disease Effectiveness Frequencies Functional Magnetic Resonance Imaging Genes Genetic Genetic Models Genetic Variation Genomics Goals Health Knowledge Marijuana Marijuana Abuse Marijuana Dependence Marijuana Smoking Mediating Methods Modeling Monitor Neurobiology Nicotine Nicotine Dependence Output Pathway interactions Patients Pharmaceutical Preparations Phase Phenotype Prevention Procedures Research Sample Size Severities Smoker Societies Substance Addiction Substance abuse problem Symptoms Testing Tobacco Variant behavior change brain behavior case control cost improved independent component analysis insertion/deletion mutation interest marijuana user multilevel analysis multimodality neuropsychological nicotine abuse simulation treatment planning

项目摘要

DESCRIPTION (provided by applicant): The goal of the proposed research is to advance the study of vulnerability to substance abuse by bridging the gap between genes and behavior via sophisticated analyses of copy number variation (CNV) and brain activation. Three substances, nicotine, alcohol, and marijuana, will be investigated using multimodality data from multiple studies. CNV covers large amounts of nucleotide sequence variation, through deletion and insertion of DNA segments ranging from 1 kilobase to several megabases. Functional magnetic resonance imaging (fMRI) provides spatially localized, neurobiological information. Behavior and neuropsychological assessments provide information about symptoms and other variables. Integrating information at different phases of progressive development of a substance disorder, a multilevel vulnerability model of substance abuse will be established to identify pathways from genes to biology and finally to behavior. The common and distinct pathways among different types of substance abuse will also be studied. The increased knowledge of how the brain interacts with genes and behavior will significantly advance the diagnosis of a substance abuse disorder and assist prevention plans via monitoring and intervening as early as possible. In addition, the knowledge of common pathways among substance abuse will improve the overall effectiveness of diagnosis, prevention and treatment. The proposed research is divided into two phases. The R21 phase will focus on development of a multivariate genomic association analysis method, termed parallel independent component analysis (ICA). The relationship between genomic CNV array data and fMRI brain activation will be accessed via the parallel ICA through simulation and real application, compared with the often-used univariate correlation test. The parallel ICA method will be implemented to data from both drinkers and smokers, and a test- replication procedure will verify the identified CNV-fMRI associations. The goal of the R33 phase is to conduct a study of vulnerability to substance abuse, including a multilevel vulnerability model from genetics to brain to behavior and common pathways among different types of substance abuse. The first step in the R33 phase is to extract all three-way relations between CNV, fMRI brain activation, and behavioral assessments. Then, the relations will be factored into a multilevel model, where consecutive CNV-brain-behavior connections and segmental relations are identified. After independently conducting the multilevel vulnerability study on alcohol, nicotine, and marijuana abuse, the common pathways among them will be extracted.

描述(申请人提供)：拟议研究的目标是通过对拷贝数变异(CNV)和大脑激活的复杂分析来弥合基因和行为之间的差距，从而推进对药物滥用易感性的研究。三种物质，尼古丁，酒精和大麻，将使用来自多项研究的多模式数据进行调查。CNV通过缺失和插入从1千碱基到数兆碱基的DNA片段，覆盖了大量的核苷酸序列变异。功能磁共振成像(FMRI)提供了空间定位的神经生物学信息。行为和神经心理评估提供有关症状和其他变量的信息。综合物质障碍发展不同阶段的信息，将建立物质滥用的多级易损性模型，以识别从基因到生物再到行为的路径。还将研究不同类型的药物滥用之间的共同和不同的途径。对大脑如何与基因和行为相互作用的了解的增加，将大大推进药物滥用障碍的诊断，并通过尽早监测和干预来协助预防计划。此外，了解药物滥用的共同途径将提高诊断、预防和治疗的整体有效性。建议的研究分为两个阶段。R21阶段将专注于开发一种多变量基因组关联分析方法，称为平行独立分量分析(ICA)。与常用的单变量相关检验相比，通过模拟和实际应用，通过并行ICA可以获得基因组CNV阵列数据与fMRI脑激活之间的关系。并行ICA方法将应用于饮酒者和吸烟者的数据，测试复制程序将验证已识别的CNV-fMRI关联。R33阶段的目标是对药物滥用的脆弱性进行研究，包括从遗传到大脑再到行为的多级脆弱性模型，以及不同类型药物滥用之间的共同路径。R33阶段的第一步是提取CNV、fMRI脑激活和行为评估之间的所有三向关系。然后，这些关系将被分解到一个多水平模型中，在该模型中，连续的CNV-脑-行为连接和节段性关系被识别。在独立进行酒精、尼古丁和大麻滥用的多层次脆弱性研究后，将提取它们之间的共同路径。