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Genetic and Epigenetic Regulation of Addiction Genes

成瘾基因的遗传和表观遗传调控

基本信息

批准号：
7916499
负责人：
WOLFGANG SADEE
金额：
$ 33.05万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-27 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7916499
关键词：
Address Affect Age Alleles Allelic Imbalance Alternative Splicing Autopsy Biogenic Amines Biological Assay Brain Brain region Candidate Disease Gene Clinical Cocaine Complex CpG Islands DRD2 gene Disease Drug Addiction Drug abuse Endowment Enzymes Epigenetic Process Evaluation Gene Expression Gene Targeting Genes Genetic Genetic Polymorphism Genetic Transcription Genotype Goals Haplotypes Human Individual Lead Measures Messenger RNA Methaqualone Methods Methylation Molecular Multivariate Analysis Pathway interactions Pattern Phenotype Physiological Play Predisposition Process Protein Isoforms Proteins Quantitative Evaluations RNA Splicing Regulation Reverse Transcriptase Polymerase Chain Reaction Role Sampling Substance abuse problem Surveys Susceptibility Gene Synapses Tissue Sample Tissues Variant addiction bisulfite brain tissue drug abuser drug addict insight mRNA Expression novel novel strategies promoter protein expression receptor repository restriction enzyme reuptake tool

项目摘要

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.

药物成瘾是一种具有强烈遗传成分的复杂疾病，而表观遗传因素的作用仍然没有解决。我们认为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，在药物成瘾中起关键作用。大一部分疑似成瘾易感基因含有CpG岛，其甲基化代表了一种可能的成瘾易感基因。主要的表观遗传机制。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脑捐赠库的组织，包含约500份可卡因和其他药物样本滥用者和年龄匹配的对照组。该储存库使相关大脑中的遗传和表观遗传研究成为可能。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（以总体表达水平表示），或以等位基因选择性方式。后者导致等位基因表达不平衡（AEI），其代表遗传和表观遗传顺式作用因子这使我们能够解决几个问题。CpG岛是如何甲基化在不同的大脑区域是不同的，个体之间的差异是什么？甲基化是否影响基因表达，交替启动子的使用，或选择性剪接？药物滥用的影响是什么在相关脑区的候选基因CpG岛甲基化？表观遗传因素有助于临床状态（成瘾）？在这个项目中，我们的目标是含有CpG岛的基因，涉及成瘾，侧重于生物胺途径，编码合成和分解代谢酶，囊泡和突触再摄取转运蛋白和受体（MAOA，MAOB，COMT，TH，DAT，NET，VMAT2， DRD2、CHRNA4）。我们已经开发出高通量的工具来测量遗传和表观遗传对mRNA和蛋白质表达的贡献以及可变剪接。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，每个因素的量化影响。这种新的方法，适用于解剖学定义的脑组织，从吸毒者和控制，有可能产生显着的洞察力的作用和相互作用，遗传和表观遗传因素之间的联系，并增加了我们对成瘾易感性的理解。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Allelic mRNA expression of sortilin-1 (SORL1) mRNA in Alzheimer's autopsy brain tissues.

DOI：
10.1016/j.neulet.2008.10.034
发表时间：
2008-12-19
期刊：
NEUROSCIENCE LETTERS
影响因子：
2.5
作者：
Alachkar, Houda;Kataki, Maria;Scharre, Douglas W.;Papp, Audrey;Sadee, Wolfgang
通讯作者：
Sadee, Wolfgang

Functional variation of the dopamine D2 receptor gene is associated with emotional control as well as brain activity and connectivity during emotion processing in humans.

DOI：
10.1523/jneurosci.3609-09.2009
发表时间：
2009-11-25
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Blasi G;Lo Bianco L;Taurisano P;Gelao B;Romano R;Fazio L;Papazacharias A;Di Giorgio A;Caforio G;Rampino A;Masellis R;Papp A;Ursini G;Sinibaldi L;Popolizio T;Sadee W;Bertolino A
通讯作者：
Bertolino A

Genetically determined measures of striatal D2 signaling predict prefrontal activity during working memory performance.

DOI：
10.1371/journal.pone.0009348
发表时间：
2010-02-22
期刊：
PloS one
影响因子：
3.7
作者：
Bertolino A;Taurisano P;Pisciotta NM;Blasi G;Fazio L;Romano R;Gelao B;Lo Bianco L;Lozupone M;Di Giorgio A;Caforio G;Sambataro F;Niccoli-Asabella A;Papp A;Ursini G;Sinibaldi L;Popolizio T;Sadee W;Rubini G
通讯作者：
Rubini G

Pharmacogenomics of the RNA world: structural RNA polymorphisms in drug therapy.