Genetic and Transcriptomic Mechanisms of Progressive Ethanol Consumption in the Diversity Outbred Mouse

多样性远交小鼠渐进性乙醇消耗的遗传和转录组机制

基本信息

批准号：
10751184
负责人：
Zachary Charles Tatom
金额：
$ 4.17万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-10 至 2025-05-09
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10751184
关键词：
Acute Adult Affect Alcohol consumption Alcohol dependence Alcohols Algorithms Amygdaloid structure Animal Model Animals Behavior Behavioral Behavioral Genetics Bioinformatics Brain Brain region Candidate Disease Gene Chromosome Mapping Chronic Complex Consumption Data Dopamine Emotions Environmental Risk Factor Equation Ethanol Functional disorder Future Gene Expression Gene Expression Profile Gene Expression Regulation Genes Genetic Genetic Models Genetic Recombination Genetic Risk Genetic Variation Genetic study Genomics Genotype Heavy Drinking Heritability Human Human Genome Individual Link Maps Mediation Modeling Molecular Morbidity - disease rate Mus Nature Neural Pathways Neurobiology Nucleus Accumbens Pathway Analysis Pathway interactions Pattern Phenotype Prefrontal Cortex Primates Quantitative Genetics Quantitative Trait Loci Research Research Personnel Resolution Rewards Risk Rodent Sampling System Testing The Jackson Laboratory Therapeutic Tissue Banks Tissue-Specific Gene Expression Training Transcript Variant Viral Vector alcohol behavior alcohol exposure alcohol use disorder candidate identification care burden career causal model causal variant design drinking effective therapy gene network genetic approach genetic architecture genetic association genome wide association study genomic locus global health human data human model mortality mouse genetics mouse model novel protein structure therapeutic target therapeutically effective trait transcriptome sequencing transcriptomics

项目摘要

Project Abstract Alcohol use disorder (AUD) poses a global healthcare burden, with significant morbidity and mortality associated with excessive alcohol consumption and effective therapeutic options still lacking. Human genome-wide association studies have recently identified genes potentially modulating alcohol consumption, but pinpointing their mechanisms of action remains difficult. Genetic variance influencing gene expression has been suggested as an additional factor in AUD but remains difficult to study in humans due to confounding environmental factors, difficulty with tissue collection and inability to conduct mechanistic manipulations. Mouse models are an effective substitute; Diversity Outbred (DO) mice from Jackson Labs display a large amount of genetic diversity and small recombination intervals, allowing for precision mapping of quantitative trait loci (QTLs). Recent research in our lab using Diversity Outbred (DO) mice identified marked variability in ethanol consumption, with a pattern of progressive ethanol intake across the DO mice and heritability ranging from 48-62%. Multiple highly significant or suggestive behavioral quantitative trait loci (bQTL) were identified for alcohol consumption phenotypes, along with unique positional candidate genes; however, determination of causal candidates and definition of mechanisms by which specific genes influence ethanol consumption have not been yet been accomplished. We hypothesize that genetic mechanisms of DO mouse ethanol consumption variance are largely driven by cognate differences in gene expression networks across PFC and NAc and that a combined behavioral and expression genetics approach can identify critical molecular mechanisms and candidate genes modulating ethanol consumption. To test this hypothesis, we aim to 1) employ an algorithm to rank candidate genes influencing ethanol consumption using RNA-seq data collected from PFC and NAc samples from DO mice, and functionally characterize gene expression networks associated with ethanol consumption; 2) derive mechanistic causal inferences about individual gene expression patterns and their relationships with ethanol consumption, and estimate direct genetic and individual gene transcript mediation effects using structural equation modeling; and 3) validate causal candidates using viral vector mouse genetic modulation of a candidate gene for ethanol consumption. These studies will provide the applicant with robust and unique training in quantitative genetics, genomic and transcriptomic analyses, and the neurobiology of alcohol, preparing him for a successful career as future independent investigator in the behavioral genetics of alcohol.

项目摘要酒精使用障碍（AUD）带来了全球医疗保健负担，发病率很高，仍然缺乏与过度饮酒和有效治疗选择相关的死亡率。人类全基因组关联研究最近已经确定了潜在调节酒精消耗的基因但是，确定其行动机制仍然很困难。影响基因表达的遗传差异具有被认为是AUD的另一个因素，但由于混淆而在人类中仍然很难研究环境因素，组织收集的困难以及无法进行机械操作。小鼠模型是有效的替代品。来自杰克逊实验室的多样性杂种（DO）小鼠展示了一个大的遗传多样性和较小的重组间隔的量，可以精确地映射定量特质基因座（QTL）。我们实验室使用多样性杂种（DO）小鼠的最新研究确定了明显的可变性乙醇的消耗，在DO小鼠中具有进步的乙醇摄入量和遗传力范围从48-62％开始。确定了多个高度显着或暗示性的行为定量性状基因座（BQTL）用于饮酒表型，以及独特的位置候选基因；但是，确定因果候选者和特定基因影响乙醇消耗的机制的定义尚未完成。我们假设小鼠乙醇消耗的遗传机制方差在很大程度上是由PFC和NAC的基因表达网络的同源差异驱动的，并且联合行为和表达遗传学方法可以鉴定关键的分子机制和调节乙醇消耗的候选基因。为了检验这一假设，我们的目的是1）采用算法使用从PFC和NAC收集的RNA-seq数据影响乙醇消耗的候选基因来自DO小鼠的样品，并在功能上表征与乙醇相关的基因表达网络消耗; 2）得出有关单个基因表达模式及其它们的机械因果推断与消耗乙醇的关系，并估计直接遗传和单个基因转录物中介使用结构方程建模的效果； 3）使用病毒载体小鼠遗传验证因果候选者调节候选基因以供乙醇消耗。这些研究将为申请人提供强大的以及定量遗传学，基因组和转录组分析以及神经生物学的独特培训酒精，为他的行为遗传学的未来独立调查员做好准备酒精。