The Heritable Transcriptome and Alcoholism

可遗传转录组和酗酒

基本信息

批准号：
9339832
负责人：
Paula Hoffman
金额：
$ 58.31万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-05 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9339832
关键词：
3&apos Untranslated Regions Acetates Alcohol consumption Alcoholism Alcohols Animal Genetics Animal Model Animals Behavior Behavioral Binding Binding Sites Biochemistry Biological Models Brain Brown Fat Candidate Disease Gene Cells Chromosome Mapping Clinical Code Communities Complex DNA Sequence Data Data Analyses Data Set Databases Development Disease Elements Embryo Environment Environmental Exposure Epidemiology Estrus Ethanol Metabolism Exons Factor Analysis Female Gene Cluster Gene Expression Generations Genes Genetic Genetic Heterogeneity Genetic Predisposition to Disease Genetic Transcription Genetic Variation Genetic study Genome Genomics Goals Grant Heart Heritability Human Human Genome Hybrids Inbred Strain Inbred Strains Rats Inbreeding Individual Informatics Laboratories Light Link Liver Maps Measures Mental Depression Methods MicroRNAs Molecular Mus Organ Organism Other Genetics Phenotype Physiological Play Polyadenylation Polygenic Traits Population Predisposing Factor Predisposition Process Protein Isoforms Publishing Quantitative Trait Loci RNA RNA Sequences Rat Strains Rattus Recombinant Inbred Strain Recombinants Regulator Genes Research Resources Resuscitation Rodent Role Scientist Site Stable Populations Swimming System Systems Analysis Techniques Testing Tissues Training Transcript Untranslated RNA Visualization software Wisconsin Work addiction alcohol use disorder animal data base cognitive ability data acquisition depression model deprivation design endophenotype gene environment interaction gene product genetic analysis genetic approach genetic association genetic variant genome database genome wide association study genomic data human disease insight interest male medical schools novel protein metabolite rat genome sex trait transcriptome web portal web site whole genome

项目摘要

The goal of this application is to establish an animal model and accompanying database suitable for a systems genetic analysis of complex traits, specifically traits that represent genetic predisposing factors for alcohol use disorder (AUD). Systems genetic approaches require a global analysis of factors such as gene expression, protein and metabolite levels in multiple tissues of an organism, as well as an understanding of gene-gene and gene-environment interactions, and the interdependency of these factors in contributing to complex traits/disorders. As a result, a key requirement for an animal model is a genetically stable population that can be studied repeatedly, over many generations, to provide cumulative data that can eventually allow for a complete systems genetic analysis. During the past grant periods, we have progressed well with the development of a Hybrid Rat Diversity Panel (HRDP) that meets these criteria. We have chosen to focus on the rat, rather than the mouse, for studies of complex traits related to AUD, because of the greater size of the rat brain, the ease of training in operant tasks, and the rat’s higher cognitive ability. We have generated DNA sequence data, RNA sequence data and whole genome exon array data on four tissues (brain, liver [whole organ and cell-specific data], heart and brown adipose tissue) from rat strains of the HXB/BXH recombinant inbred (RI) panel and from classic inbred rat strains. We have mapped QTLs for behavioral/physiological traits (alcohol consumption, alcohol deprivation effect, alcohol metabolism including acetate levels after alcohol administration), as well as used transcriptome data to map expression QTLs, to generate transcript coexpression modules and map module eigengene (first principal component) QTLs. These data have been used to identify candidate genes and transcriptional networks that contribute to the measured biochemistry and behaviors. All of our raw, processed and analyzed data have been made available to the research community on our PhenoGen website (http://phenogen.ucdenver.edu). This website, that we developed, also includes several visualization tools to explore these data in a systems genetics framework and allows the user to observe genetic relationships between a complex phenotype of interest and networks of gene products that influence the phenotype. We are now proposing to complete the main core of transcriptional data for the 96- strain HRDP, adding data from another rat RI panel (FXLE/LEXF) and more inbred rat strains. We will obtain full transcriptome information of brain and liver of male and female rats from all strains, quantify the expression of transcript isoforms, including 3’UTR isoforms, and analyze the 3’UTR regions for alternative use of polyadenylation sites and miRNA binding sites. We will use our established and newly developed pipelines to disseminate integrated, systems level data (PhenoGen and Rat Genome Database). We will also expand our demonstration for applying the gathered information to the identification of genetic factors that are linked to the development of AUD by obtaining information on predisposition to “depression” in the HXB/BXH RI panel, and we will continue to integrate the animal data with human GWAS data.

该应用程序的目标是建立适合系统的动物模型和随附数据库对复杂性状的遗传分析，特别是代表饮酒遗传易感因素的性状系统遗传学方法需要对基因表达等因素进行全局分析，生物体多个组织中的蛋白质和代谢水平，以及对基因与基因的理解基因与环境的相互作用，以及这些因素在促成复杂的过程中的相互依赖性因此，动物模型的一个关键要求是遗传稳定的群体。经过几代人的反复研究，以提供最终可以实现的累积数据在过去的资助期间，我们在完整的系统遗传分析方面取得了良好的进展。我们选择专注于开发符合这些标准的混合大鼠多样性小组 (HRDP)。使用大鼠而不是小鼠来研究与 AUD 相关的复杂性状，因为大鼠的尺寸更大我们已经生成了老鼠的大脑、操作任务训练的容易程度以及老鼠更高的认知能力。四种组织（脑、肝[全基因组]的序列数据、RNA序列数据和全基因组外显子阵列数据） HXB/BXH 重组大鼠品系的器官和细胞特异性数据]、心脏和棕色脂肪组织）近交 (RI) 面板和经典近交大鼠品系我们已经绘制了行为/生理特征的 QTL。（饮酒剥夺效应、酒精代谢，包括饮酒后的醋酸水平管理），以及使用转录组数据来绘制表达 QTL，以生成转录本共表达模块和图谱模块特征基因（第一主成分）QTL。用于识别有助于测量的生物化学和转录网络的候选基因和转录网络我们所有的原始、处理和分析数据都已提供给研究界。我们开发的该网站还包括我们的 PhenoGen 网站 (http://phenogen.ucdenver.edu)。多种可视化工具可在系统遗传学框架中探索这些数据，并允许用户观察感兴趣的复杂表型与基因产物网络之间的遗传关系我们现在建议完成96-转录数据的主要核心。 HRDP 品系，添加来自另一个大鼠 RI 组 (FXLE/LEXF) 和更多近交大鼠品系的数据，我们将获得。所有品系雄性和雌性大鼠大脑和肝脏的完整转录组信息，量化表达转录亚型，包括 3'UTR 亚型，并分析 3'UTR 区域以供替代使用我们将使用我们已建立的和新开发的管道来进行多聚腺苷酸化位点和 miRNA 结合位点。传播集成的系统级数据（PhenoGen 和大鼠基因组数据库）。演示如何应用收集到的信息来识别与该疾病相关的遗传因素通过获取 HXB/BXH RI 面板中有关“抑郁”倾向的信息来制定 AUD，以及我们将继续将动物数据与人类 GWAS 数据整合。