Functional Genomics and Epigenomics in HIV of Longitudinal Injection Drug Use Trajectory

HIV纵向注射吸毒轨迹的功能基因组学和表观基因组学

基本信息

批准号：
9045601
负责人：
Brion S Maher
金额：
$ 64.38万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-15 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9045601
关键词：
Abstinence Acetylation Acquired Immunodeficiency Syndrome Acute Address Adult African American Age Alcohol consumption Alcohol or Other Drugs use American Animal Model Anxiety Baltimore Biological Biology Brain Brain region Cause of Death Cessation of life ChIP-seq Chronic Cocaine Communities DNA Methylation DNA Sequence Data Data Set Dependence Diagnosis Disease Drug Addiction Drug Exposure Drug Use Disorder Drug usage Drug user Enrollment Epigenetic Process Ethnic Origin European Exhibits Exposure to Family Frequencies Funding Genetic Genetic Variation Genomics Genotype HIV Health Heroin Histone Acetylation Human Illicit Drugs Immunoglobulin Variable Region Individual Injecting drug user Injection of therapeutic agent Institutes Interview Intoxication Intravenous Investigation Knowledge Life Experience Link Literature Longitudinal Studies Measures Mediating Mental Depression Mental disorders Methylation Modeling Modification National Institute of Drug Abuse Nicotine Dependence Opiates Outcome Pathway interactions Pattern Peripheral Pharmaceutical Preparations Phenotype Physiological Prefrontal Cortex Process Relapse Research Research Personnel Risk Risk Behaviors Role Sampling Severities Signal Transduction Site Specificity Substance Use Disorder Technology Testing Time Tissues Toxicology Variant Weight Work addiction base bead chip caffeine dependence cohort driving force drug abstinence drug of abuse epigenetic marker epigenetic variation epigenomics experience follow-up functional genomics genetic variant genome wide association study genome wide methylation genome-wide histone methylation histone modification informant injection drug use innovation interest intravenous drug use intravenous drug user novel prospective public health relevance response sex trait

项目摘要

DESCRIPTION (provided by applicant): We propose a comprehensive investigation into the relationship between epigenetic variation (DNA Methylation, Histone Methylation and Acetylation), genome-wide, and variation in intravenous drug use in the ALIVE cohort. The AIDS Linked to the Intravenous Experience (ALIVE) study is a prospective community-based cohort of intravenous drug users (IDUs) in Baltimore that commenced in 1988, eventually enrolling more than 3,500 IDUs. Subsequent biennial follow-up included comprehensive assessment of risk behaviors and drug use. We will focus our work on the HIV- subjects in the sample who were already genotyped using the Affymetrix 6.0 platform (N~1200). This sample is >95% African- American addressing a common shortcoming in genomics research. In Aim 1, we propose to examine the relationship between DNA methylation, assessed genome-wide using the Illumina Methylation 450k bead chip, and intravenous drug use, in a subset with available longitudinal biological samples during extended periods of chronic use and then again > 1 year after complete abstinence from all illicit drugs. This is an extension of a preliminary study, presented in the Research Plan, where we found a significant impact of IDU on genome-wide methylation. We will also perform this work on a subsample with subsequent relapse to uncover methylation signals which differ between those who relapse (Aim 1.2) and those who continue to abstain as well as examine the role of methylation in early drug use cessation (Aim 1.3). In Aim 2, we extend this work to examine the impact of long-term chronic use, operationalized as `injection years', on genome-wide methylation signals. Aim 3, we examine the relationship between Histone Methylation (H3K9me2) and Acetylation (H3K9ac) using ChIP Seq technology. As in Aim 1, we will select longitudinal samples from the same individuals during periods of chronic IDU and complete abstinence to maximize the likelihood that we will find differences. We will also attempt to replicate the top findings in a post-mortem brain sample comparing opiate users to controls. This work is novel and innovative for several reasons. The proposed work is among the largest epigenetic studies for any disease or trait in an African American sample. The work builds on a large literature based on animal models of drug exposure for which there are a limited number of human datasets, with available biological samples during periods of chronic use and complete abstinence that could attempt similar work. Lastly, given that we have existing GWAS data, this work will be truly integrative, across many domains of biology (genetic, epigenetic, and phenotypic).

描述（由应用提供）：我们提出了对表观遗传变异（DNA甲基化，组蛋白甲基化和乙酰化）之间的关系，全基因组和静脉药物使用的变异之间的关系。与静脉经历（Alive）研究相关的艾滋病是巴尔的摩的一个前瞻性社区静脉吸毒者（IDU）的同类，该队列于1988年开始，最终招收了3500多个IDU。随后的双年展随访包括对风险行为和药物使用的全面评估。我们将把工作集中在样本中的HIV受试者上，这些受试者已经使用Affymetrix 6.0平台（N〜1200）进行了基因分型。该样本> 95％的非裔美国人，解决了基因组学研究中常见的缺点。在AIM 1中，我们建议在一个子集中，使用Illumina甲基化450k珠芯片评估DNA甲基化，使用Illumina甲基化450K珠芯片评估基因组之间的关系，并在长期使用的纵向生物学时期内，在延长的纵向生物学样本中，然后在所有非法药物中完全戒烟后再次> 1年。这是研究计划中提出的初步研究的扩展，在那里我们发现IDU对全基因组甲基化产生了重大影响。我们还将在子样本上进行这项工作，随后缓解甲基化信号，这些信号（AIM 1.2）与那些继续弃用的人之间有所不同，并检查了甲基化在早期药物使用中的作用（AIM 1.3）。在AIM 2中，我们扩展了这项工作，以研究长期长期使用（注射年度”对全基因组甲基化信号的影响。 AIM 3，我们使用芯片SEQ技术研究了组蛋白甲基化（H3K9ME2）和乙酰化（H3K9AC）之间的关系。与AIM 1一样，我们将在慢性IDU期间选择来自同一个人的纵向样本，并完全节制，以最大程度地提高我们发现差异的可能性。我们还将尝试在验尸大脑样本中复制最高发现，以比较扩展器用户与控件。这项工作是新颖而创新的，原因有几个。拟议的工作是非裔美国人样本中任何疾病或性状的最大表观遗传学研究之一。这项工作基于大型文献，基于动物暴露的动物模型，其人类数据集数量有限，在长期使用期间，可用的生物学样本和完全戒酒，可以尝试类似的工作。最后，鉴于我们有现有的GWAS数据，这项工作将在许多生物学领域（遗传，表观遗传学和表型）中真正整合在一起。