The Heritable Transcriptome and Alcoholism

可遗传转录组和酗酒

• 批准号: 9757647
• 负责人: Paula Hoffman
• 金额: $ 66.31万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 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/9757647
• 关键词: 3' 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; System; Systems Analysis; Techniques; Tissues; Training; Transcript; Untranslated RNA; Visualization software; Wisconsin; Work; addiction; alcohol use disorder; analysis pipeline; animal data; base; cognitive ability; data acquisition; depression model; deprivation; design; endophenotype; forced swim test; 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

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.

该应用的目的是建立适合系统的动物模型和参与数据库 复杂性状的遗传分析，特别是代表饮酒遗传因素的特征 障碍（AUD）。系统遗传方法需要全球分析基因表达等因素， 蛋白质和代谢物在生物体的多次中，以及对基因基因和 基因环境相互作用，以及这些因素在有助于复杂的方面的相互依赖性 特质/疾病。结果，动物模型的关键要求是一个普遍稳定的人群 再次研究多代人，以提供有时可以允许的累积数据 完整的系统遗传分析。在过去的赠款期间，我们在 符合这些标准的混合大鼠多样性面板（HRDP）的开发。我们选择专注于 大鼠而不是小鼠，用于研究与AUD相关的复杂性状的研究，因为 老鼠的大脑，操作任务的训练便利性以及老鼠更高的认知能力。我们已经产生了DNA 序列数据，RNA序列数据和整个基因组外显子阵列数据四个时间（大脑，肝脏[整个时间） 来自HXB/BXH重组的大鼠菌株的器官和细胞特异性数据]，心脏和棕色脂肪组织） 近交（RI）面板和经典的近交大鼠菌株。我们为行为/生理特征绘制了QTL （酒精消耗，酒精剥夺效果，酒精代谢，包括醋酸盐水平 管理）以及使用的转录组数据来映射表达式QTL，以生成成绩单 共表达模块和MAP模块本元（第一个主要组件）QTL。这些数据已经 用于识别候选基因和转录网络，这些网络有助于测得的生物化学和 行为。我们的所有原始，经过处理和分析的数据都已提供给研究社区 在我们的苯植物网站（http://phenogen.ucdenver.edu）上。我们开发的网站也包括 几种可视化工具可以在系统遗传学框架中探索这些数据，并允许用户 观察复杂的感兴趣表型与基因产物网络之间的遗传关系 影响表型。我们现在建议完成96-的转录数据的主要核心 菌株HRDP，添加来自另一个大鼠RI面板（FXLE/LEXF）的数据和更多的近交大鼠菌株。我们将获得 来自各种菌株的雄性和雌性大鼠的大脑和肝脏的完整转录组信息，量化表达 成绩单同工型，包括3'UTR同工型，并分析3'UTR区域以替代使用 聚腺苷酸位点和miRNA结合位点。我们将使用我们已建立的新开发的管道来 传播集成的系统级数据（苯基和大鼠基因组数据库）。我们还将扩大我们的 演示将收集的信息应用于与遗传因素的识别 通过获取有关HXB/BXH RI面板中“抑郁症”易感性的信息来开发AUD，并且 我们将继续将动物数据与人类GWAS数据相结合。