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（由申请人提供）：我们建议对 ALIVE 队列中的表观遗传变异（DNA 甲基化、组蛋白甲基化和乙酰化）、全基因组和静脉药物使用变异之间的关系进行全面调查。 (ALIVE) 研究是巴尔的摩一项基于社区的静脉吸毒者 (IDU) 前瞻性队列研究，于 1988 年开始，最终招募了超过随后的两年期随访包括对 3,500 名注射吸毒者进行风险行为和药物使用的综合评估。我们将重点关注样本中已使用 Affymetrix 6.0 平台进行基因分型的 HIV 受试者（N~1200）。 95% 的非裔美国人解决了基因组学研究中的一个常见缺陷在目标 1 中，我们建议检查 DNA 甲基化之间的关系，并使用 Illumina 甲基化评估全基因组。 450k 珠芯片和静脉注射药物使用，在长期使用期间的纵向可用生物样本中，然后在完全戒除所有非法药物后再次>1年这是研究中提出的一项初步研究的延伸。计划，我们发现 IDU 对全基因组甲基化有显着影响，我们还将对随后复发的子样本进行这项工作，以发现复发者（目标 1.2）和复发者之间的甲基化信号不同。那些继续戒毒的人以及研究甲基化在早期戒毒中的作用（目标 1.3）。在目标 2 中，我们将这项工作扩展到研究长期长期使用（可操作为“注射年”）对药物的影响。目标 3，我们使用 ChIP Seq 技术检查组蛋白甲基化 (H3K9me2) 和乙酰化 (H3K9ac) 之间的关系。 1，我们将在慢性注射吸毒和完全戒断期间从同一个人中选择纵向样本，以最大限度地提高我们发现差异的可能性。我们还将尝试在比较阿片类药物使用者和对照组的死后大脑样本中复制最重要的发现。这项工作具有新颖性和创新性，其原因有几个。人类数据集的数量，以及可用的生物学最后，鉴于我们拥有现有的 GWAS 数据，这项工作将真正跨生物学的许多领域（遗传、表观遗传和表型）进行整合。