The Heritable Transcriptome and Alcoholism

可遗传转录组和酗酒

• 批准号: 10224715
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224715
• 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 Genome Database; 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; data dissemination; depression model; deprivation; design; endophenotype; forced swim test; gene environment interaction; gene product; genetic analysis; genetic approach; genetic association; genetic variant; genome wide association study; genomic data; human disease; insight; interest; male; medical schools; novel; protein metabolite; 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.

本应用程序的目标是建立一个适合系统的动物模型和相应的数据库

项目成果

The multiMiR R package and database: integration of microRNA-target interactions along with their disease and drug associations.

• DOI: 10.1093/nar/gku631
• 发表时间: 2014
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Ru Y;Kechris KJ;Tabakoff B;Hoffman P;Radcliffe RA;Bowler R;Mahaffey S;Rossi S;Calin GA;Bemis L;Theodorescu D
• 通讯作者: Theodorescu D

A long non-coding RNA (Lrap) modulates brain gene expression and levels of alcohol consumption in rats.

• DOI: 10.1111/gbb.12698
• 发表时间: 2021-03
• 期刊: Genes, brain, and behavior
• 作者: Saba LM;Hoffman PL;Homanics GE;Mahaffey S;Daulatabad SV;Janga SC;Tabakoff B
• 通讯作者: Tabakoff B

Sex-specific role for adenylyl cyclase type 7 in alcohol dependence.

• DOI: 10.1016/j.biopsych.2011.01.037
• 发表时间: 2011-06-01
• 期刊: BIOLOGICAL PSYCHIATRY
• 影响因子: 10.6
• 作者: Desrivieres, Sylvane;Pronko, Sergey P.;Lourdusamy, Anbarasu;Ducci, Francesca;Hoffman, Paula L.;Wodarz, Norbert;Ridinger, Monika;Rietschel, Marcella;Zelenika, Diana;Lathrop, Mark;Schumann, Gunter;Tabakoff, Boris
• 通讯作者: Tabakoff, Boris

Voluntary exposure to a toxin: the genetic influence on ethanol consumption.

• DOI: 10.1007/s00335-017-9726-3
• 发表时间: 2018-03
• 期刊: Mammalian genome : official journal of the International Mammalian Genome Society
• 作者: Hoffman PL;Saba LM;Vanderlinden LA;Tabakoff B
• 通讯作者: Tabakoff B

Networking in Biology: The Hybrid Rat Diversity Panel.

• DOI: 10.1007/978-1-4939-9581-3_10
• 发表时间: 2019
• 期刊: Methods in molecular biology
• 作者: B. Tabakoff;Harry Smith;L. Vanderlinden;P. Hoffman;L. Saba