Genetic and Epigenetic Regulation of Addiction Genes

成瘾基因的遗传和表观遗传调控

• 批准号: 7172872
• 负责人: WOLFGANG SADEE
• 金额: $ 36.61万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-27 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7172872
• 关键词: CpG islands; alleles; brain; clinical research; drug addiction; epigenetics; gene expression; genes; genetics; methylation; role; tissues

Drug addiction is a complex disorder with a strong genetic component, while the role of epigenetic factors remains unresolved. We propose that the interplay between genetic polymorphisms and epigenetic changes determines gene expression and possibly mRNA processing, serving a critical role in drug addiction. A large portion of suspected addiction susceptibility genes harbors CpG islands, methylation of which represents a main epigenetic mechanism. Both genetic and epigenetic factors likely contribute to addiction susceptibility and physiological changes occurring as a result of substance abuse. We will study these factors in autopsy tissues from the Miami Brain Endowment Bank, containing ~approximately 500 samples from cocaine and other drug abusers and age-matched controls. This repository enables genetic and epigenetic studies in relevant brain regions involved in addiction. CpG methylation can occur randomly between the two allele of a gene (represented in overall expression level), or in an allele-selective fashion. The latter causes an allelic expression imbalance (AEI), which represents a precise and quantitative phenotype for both genetic and epigenetic cis-acting factors. This permits us to address several questions. How does CpG island methylation vary across brain regions, and what is the variability among individuals? Does methylation affect gene expression, alternate promoter usage, or alternative splicing? What is the effect of substance abuse on CpG island methylation in candidate genes, in relevant brain regions? Do epigentic and genetic factors contribute to clinical status (addiction)? In this project, we target genes harboring CpG islands that are implicated in addiction, focusing on biogenic amine pathways, encoding synthetic and catabolic enzymes, vesicular and synaptic reuptake transporters, and receptors (MAOA, MAOB, COMT, TH, DAT, NET, VMAT2, DRD2, CHRNA4). We have developed high-throughput tools for measuring the genetic and epigenetic contribution to mRNA and protein expression, and alternative splicing. Our assays are allele-specific, enabling the evaluation of genetic and epigenetic factors in allelic expression, a powerful tool for assessing the quantitative impact of each factor. This novel approach, applied to anatomically defined brain tissues from drug addicts and controls, has the potential to yield significant insight into the role of and interplay between genetic and epigenetic factors, and add to our understanding of susceptibility to addiction.

药物成瘾是一种复杂的疾病，具有很强的遗传成分，而表观遗传因素的作用 仍未解决。我们提出遗传多态性和表观遗传变化之间的相互作用 决定基因表达和可能的 mRNA 加工，在药物成瘾中发挥关键作用。一个大 部分疑似成瘾易感基因含有 CpG 岛，其甲基化代表 主要表观遗传机制。遗传和表观遗传因素都可能导致成瘾易感性 以及由于药物滥用而发生的生理变化。我们将在尸检中研究这些因素 来自迈阿密大脑捐赠银行的组织，包含大约 500 个可卡因和其他药物的样本 施虐者和年龄匹配的控制。该存储库能够在相关大脑中进行遗传和表观遗传研究 涉及成瘾的区域。 CpG 甲基化可以在基因的两个等位基因之间随机发生 （以整体表达水平表示），或以等位基因选择性方式。后者导致等位基因 表达失衡（AEI），代表遗传和基因的精确和定量的表型 表观遗传顺式作用因子。这使我们能够解决几个问题。 CpG岛如何 甲基化因大脑区域而异，个体之间的差异是什么？甲基化有影响吗 基因表达、替代启动子使用或替代剪接？滥用药物有什么影响 相关大脑区域候选基因中 CpG 岛甲基化的影响？有表观遗传因素和遗传因素吗 有助于临床状态（成瘾）？在这个项目中，我们的目标基因含有 CpG 岛，这些岛是 与成瘾有关，专注于生物胺途径，编码合成酶和分解代谢酶， 囊泡和突触再摄取转运蛋白和受体（MAOA、MAOB、COMT、TH、DAT、NET、VMAT2、 DRD2、CHRNA4)。我们开发了用于测量遗传和表观遗传的高通量工具 对 mRNA 和蛋白质表达以及选择性剪接的贡献。我们的检测是等位基因特异性的， 能够评估等位基因表达中的遗传和表观遗传因素，这是评估等位基因表达的强大工具 每个因素的定量影响。这种新颖的方法适用于解剖学上定义的脑组织 来自吸毒者和控制者的研究，有可能对吸毒者的作用和相互作用产生重要的见解 遗传和表观遗传因素之间的关系，并增加我们对成瘾易感性的理解。