Genetic and Epigenetic Analysis of Alcohol Self-Administration in Monkeys

猴子酒精自我管理的遗传和表观遗传分析

基本信息

批准号：
8607103
负责人：
BETSY M FERGUSON
金额：
$ 25.46万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-15 至 2017-01-13
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8607103
关键词：
Alcohol abuse Alcohol consumption Alcoholism Alcohols Alleles Animal Model Animals Blood Brain Candidate Disease Gene Chronic Corticotropin DNA DNA Methylation DNA Modification Process Dexamethasone Dopamine Endocrine Environmental Risk Factor Epigenetic Process Ethanol Exons Functional disorder Future Gene Expression Gene-Modified Genes Genetic Genetic Predisposition to Disease Genetic Variation Genome Genomic DNA Genotype Grant Haplotypes Heavy Drinking Human Hydrocortisone Hypermethylation Immunoprecipitation Individual Life Stress Link Longitudinal Studies Macaca mulatta Measures Methods Methylation Modeling Modification Monitor Monkeys Neurosecretory Systems Neurotransmitters Opioid Pathway interactions Pattern Peripheral Blood Mononuclear Cell Population Prefrontal Cortex Primates Recording of previous events Regulation Reporting Research Research Design Risk Self Administration Serotonin Signal Pathway Stressful Event Technology Testing Tissue Sample Tissues Translating Variant addiction alcohol exposure alcohol risk alcohol use disorder alcoholism therapy allostasis base biological adaptation to stress bisulfite brain tissue chronic alcohol ingestion cohort genetic variant hypothalamic-pituitary-adrenal axis monoamine next generation sequencing nonhuman primate novel novel strategies problem drinker response risk variant

项目摘要

DESCRIPTION (provided by applicant): This proposal investigates the implication of both genetic variation and epigenetic modification on HPA axis regulation and excessive alcohol consumption in primates. These studies will draw upon the rhesus macaque ethanol self-administration model, which will enable a longitudinal study design examining genomic DNA methylation before and after 12 months of ethanol consumption, accurate measure of ethanol intake and endocrine levels, and access to both blood and brain tissue samples for the comparison of epigenetic changes in both tissues. We will use whole-genome approaches to measure CpG methylation levels in the tissues before and after chronic ethanol consumption. We will test whether changes in methylation levels are associated with corresponding changes in gene expression. We will also test whether changes in methylation patterns in the blood parallel those found in the brain. Also taking advantage of the high efficiency of next generation sequencing technology, we will sequence neurotransmitter genes from the HPA axis and monoamine signaling pathways in a large cohort of animals. We will test the association between common variants and endocrine dysfunction, and will evaluate potential additive effects and interactions between "risk" alleles in multiple signaling pathways. We will also explore whether there is an association between specific alleles or haplotypes and changes in methylation following chronic alcohol consumption (allele-specific methylation). Together, these approaches will provide a comprehensive basis for evaluating the cumulative genetic vulnerabilities that contribute to excessive alcohol use. Owing to the close evolutionary relationship of non-human primates, these studies will have a high-degree of translational relevance to human alcoholism, potentially 1) identifying alcohol-linked epigenetic modification of genes, 2) determining the relevance of epigenetic modifications in a clinically accessible tissue (blood) to those in the brain and 3) suggesting novel targets for the future treatment of alcohol use disorders.

描述（由申请人提供）：该提案研究了遗传变异和表观遗传修饰对HPA轴调节的影响，而灵长类动物的饮酒过量。这些研究将借鉴猕猴的乙醇自我给药模型，该模型将在12个月的乙醇消耗前后进行纵向研究设计，研究基因组DNA甲基化，准确测量乙醇摄入和内分泌水平的准确度量，并访问血液和脑组织样品，以比较两种组织中的表观遗传学变化。我们将使用全基因组方法来测量慢性乙醇消耗前后组织中组织中的CpG甲基化水平。我们将测试甲基化水平的变化是否与基因表达的相应变化有关。我们还将测试是否在大脑中发现的血液中甲基化模式的变化。还利用下一代测序技术的高效率，我们将在大量动物队列中从HPA轴和单胺信号通路进行序列神经递质基因。我们将测试常见变体和内分泌功能障碍之间的关联，并将评估多个信号通路中“风险”等位基因之间的潜在添加剂效应和相互作用。我们还将探讨特定等位基因或单倍型之间是否存在关联，以及慢性酒精消耗后甲基化的变化（等位基因特异性甲基化）。这些方法一起，将为评估有助于过度饮酒的累积遗传脆弱性提供全面的基础。由于非人类灵长类动物的密切进化关系，这些研究将具有与人类酒精中毒的转化相关性，可能是1）确定基因的酒精连接的表观遗传修饰，2）确定表观遗传修饰在临床上可访问的组织（血液）中与大脑中的靶标（血液）中的相关性，并建议在大脑中使用新颖的靶标的未来的饮酒。