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Exploiting zebrafish genetics to identify genes affecting addiction-related phenotypes.

利用斑马鱼遗传学来识别影响成瘾相关表型的基因。

基本信息

批准号：
9751829
负责人：
Caroline Helen Brennan
金额：
$ 42.82万
依托单位：
UNIV/LONDON-QUEEN MARY& WESTFIELD COLL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751829
关键词：
Adult Affect Alcohols Alleles Animal Model Behavior Behavioral Behavioral Assay Behavioral Genetics Biological Factors Biological Process Biology Breeding CRISPR/Cas technology Candidate Disease Gene Cardiovascular Diseases Cause of Death Cell physiology Cells Cessation of life Chronic Data Development Developmental Gene Disease Drug Addiction Epidemic Evolution Family Fishes Future Gene Expression Gene Expression Profiling Generations Genes Genetic Genetic Models Genetic Risk Genetic Screening Genetic Variation Genome Genotype Goals Health Care Costs Heritability Human Human Genetics Human Genome Impulsivity Individual Knock-out Malignant Neoplasms Maps Mediating Mental disorders Microarray Analysis Modeling Mutagenesis Mutation Nicotine Nicotine Dependence Outcome Outcome Study Pathway interactions Phenotype Population Predisposition Reaction Time Regulator Genes Research Rewards Risk Siblings Smoking Substance abuse problem System Testing Time Tobacco Tobacco Dependence Variant Vertebrates Work World Health Organization Zebrafish addiction causal variant cost density developmental genetics drug of abuse drug reward exome sequencing gene function genome wide association study improved individualized medicine insight mutant neural circuit neural patterning neuronal patterning next generation sequencing nicotine exposure novel personalized medicine population based preference programs protein function response screening smoking addiction transcriptome sequencing treatment strategy

项目摘要

Exploiting zebrafish genetics to identify genes affecting addiction-related phenotypes The cost of substance abuse in the US alone is estimated at $166 billion annually in preventable health care costs, with tobacco ($130 billion) and alcohol ($25 billion) abuse contributing to the overwhelming majority of this expense. The World Health Organization declared tobacco-related disease a global epidemic, predicted to cause an estimated 8 million annual deaths worldwide by 2030, if unabated. There is a vital need for increased understanding of the genetic and cell biological factors influencing vulnerability to addiction including smoking to help identify individuals at risk and to inform treatment strategies. As approaches to identify genetic risk are difficult in humans, research on genetic risk can be facilitated by the use of animal models. Zebrafish are an established developmental and behavioral genetic model species that show conserved responses to common drugs of abuse as well as behaviors that model core phenotypes predictive of vulnerability to addiction. We shall identify genes affecting core phenotypes associated with addiction by screening lines of ethyl nitrosurea (ENU)-mutagenised zebrafish for sensitivity to nicotine reward and impulsivity. We test the hypothesis that genes that show persistent adaptive changes in expression following chronic nicotine exposure are also addiction vulnerability genes. Our specific aims are: 1) To isolate 25 heritable loci affecting a) nicotine reward and b) impulsivity. i) We will use behavioral assays in adult ENU-mutagenized zebrafish to identify families showing altered nicotine reward and impulse control. We have developed a scalable, fully automated behavioral assay system for this purpose. We will use analysis of microarray or RNAseq data to identify genes that show persistent changes in expression following chronic nicotine exposure as candidates for genes affecting nicotine addiction vulnerability. We will pre-load the screen with families carrying mutations in these candidate genes. ii) We shall use exome sequencing to map the mutations in at least 10 families. The use of ENU- mutagenized lines facilitates identification of the causal mutations (by generation of strong phenotypes and/or by the ENU mutations acting as markers). 2) To identify the cell biological processes underlying the observed behavioral phenotypes. i) We shall use additional (predicted functional) ENU mutations or targeted knockouts of the identified genes to confirm genotype-phenotype associations. ii) We shall perform RNA sequencing to gain insight into possible effects on gene expression and cellular pathways affected. iii) We shall perform developmental analyses to test the hypothesis that behavioral effects are mediated by effects on neuronal patterning or neural circuit formation at developmental timepoints. The expected outcomes from this study are identification of novel genetic factors influencing core behaviors predictive of vulnerability to drug addiction and increased understanding of the cellular processes affected. These findings will enable future human genetic variation studies in these identified genes, with the potential to develop more personalized therapies. Results from this work will have a positive impact on individualized treatment efforts for tobacco dependence and addiction as a whole.

利用斑马鱼基因鉴定影响成瘾相关表型的基因