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。

• 批准号: 10460608
• 负责人: Caroline Helen Brennan
• 金额: $ 41.9万
• 依托单位: UNIV/LONDON-QUEEN MARY& WESTFIELD COLL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10460608
• 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 Dependence; Outcome; Outcome Study; Pathway interactions; Phenotype; Population; Predisposition; Reaction Time; Regulator Genes; Research; Risk; Siblings; Smoking; Substance abuse problem; System; Testing; Time; Tobacco; Tobacco Dependence; Variant; Vertebrates; Work; World Health Organization; Zebrafish; addiction; behavioral phenotyping; causal variant; conditioned place preference; cost; cost estimate; 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; nicotine reward; novel; personalized medicine; population based; programs; protein function; response; screening; smoking addiction; transcriptome sequencing; treatment strategy

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

项目成果

Ankk1 Loss of Function Disrupts Dopaminergic Pathways in Zebrafish.

• DOI: 10.3389/fnins.2022.794653
• 发表时间: 2022
• 期刊: Frontiers in neuroscience
• 影响因子: 4.3
• 作者: Leggieri A;García-González J;Torres-Perez JV;Havelange W;Hosseinian S;Mech AM;Keatinge M;Busch-Nentwich EM;Brennan CH
• 通讯作者: Brennan CH

Conservation of mechanisms regulating emotional-like responses on spontaneous nicotine withdrawal in zebrafish and mammals.

• DOI: 10.1016/j.pnpbp.2021.110334
• 发表时间: 2021-12-20
• 期刊: Progress in neuro-psychopharmacology & biological psychiatry
• 影响因子: 5.6
• 作者: Ponzoni L;Melzi G;Marabini L;Martini A;Petrillo G;Teh MT;Torres-Perez JV;Morara S;Gotti C;Braida D;Brennan CH;Sala M
• 通讯作者: Sala M

Increased Response to 3,4-Methylenedioxymethamphetamine (MDMA) Reward and Altered Gene Expression in Zebrafish During Short- and Long-Term Nicotine Withdrawal.

• DOI: 10.1007/s12035-020-02225-5
• 发表时间: 2021-04
• 期刊: Molecular neurobiology
• 影响因子: 5.1
• 作者: Ponzoni L;Teh MT;Torres-Perez JV;Brennan CH;Braida D;Sala M
• 通讯作者: Sala M

Translational relevance of forward genetic screens in animal models for the study of psychiatric disease.

远期遗传筛选在动物模型中的转化相关性，用于研究精神病。

• DOI: 10.1016/j.neubiorev.2022.104559
• 发表时间: 2022-04
• 期刊: NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS
• 影响因子: 8.2
• 作者: Sheardown, Eva;Mech, Aleksandra M.;Petrazzini, Maria Elena Miletto;Leggieri, Adele;Gidziela, Agnieszka;Hosseinian, Saeedeh;Sealy, Ian M.;Torres-Perez, Jose, V;Busch-Nentwich, Elisabeth M.;Malanchini, Margherita;Brennan, Caroline H.
• 通讯作者: Brennan, Caroline H.

Behavioral Effects of Developmental Exposure to JWH-018 in Wild-Type and Disrupted in Schizophrenia 1 (disc1) Mutant Zebrafish.

• DOI: 10.3390/biom11020319
• 发表时间: 2021-02-19
• 期刊: Biomolecules
• 影响因子: 5.5
• 作者: García-González J;de Quadros B;Havelange W;Brock AJ;Brennan CH
• 通讯作者: Brennan CH