Identification of Genetic Variants that Contribute to Compulsive Cocaine Intakein Rats

鉴定导致大鼠强迫性可卡因摄入的遗传变异

• 批准号: 10457170
• 负责人: Olivier George
• 金额: $ 71.04万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10457170
• 关键词: Alcohol abuse; Animal Genetics; Animal Model; Animals; Behavior; Behavioral; Behavioral Genetics; Biological; Brain; Brain region; Chronic; Cocaine; Cocaine Dependence; Cocaine use disorder; Code; Collaborations; Communities; Complex; Computer software; Computerized Medical Record; Data; Documentation; Environment; Epigenetic Process; Female; Foundations; Gene Expression; Genetic; Genomics; Genotype; Goals; Gold; Heritability; Human; Human Genome; Incidence; Individual; Infrastructure; Intake; Intravenous; Investigation; Lead; Machine Learning; Methodology; Modeling; Molecular; National Institute of Drug Abuse; Nucleotides; Outcome; Phenotype; Physiology; Population; Procedures; Quantitative Trait Loci; Rattus; Research; Research Personnel; Resistance; Resources; Sample Size; Sampling; Self Administration; Standardization; Substance Addiction; Substance Use Disorder; Substance abuse problem; Tandem Repeat Sequences; Tissue Banks; Tissues; United States National Institutes of Health; Variant; Video Recording; addiction; base; behavioral phenotyping; biobank; cocaine exposure; cocaine self-administration; cocaine use; comorbidity; data integration; deep neural network; endophenotype; follow-up; genetic analysis; genetic variant; genome sequencing; genome wide association study; genomic locus; improved; longitudinal analysis; male; multidisciplinary; multiple omics; new therapeutic target; next generation; next generation sequencing; nicotine abuse; novel; novel strategies; pre-clinical; programs; screening; screening program; substance use; trait; transfer learning

Abstract The purpose of the NIDA Animal Genetics Program is to identify genetic, genomic, epigenetic variants, physiology and brain functions that contribute to addiction-like behaviors, related behavioral endophenotypes, and behavioral comorbidities to substance use disorder. During the past four years, our multidisciplinary and highly collaborative consortium has been identifying gene variants that are associated with increased vulnerability to compulsive-like cocaine use by performing the first GWAS using an advanced model of chronic intravenous cocaine self-administration in N/NIH heterogeneous stock (HS). We have also created the first preclinical cocaine biobank which enables researchers who do not have the resources to perform chronic intravenous self-administration or next-generation genome sequencing to perform advanced genetic, molecular, and cellular studies to further our understanding of the biological changes underlying addiction-like behaviors. While these efforts have been very successful in achieving the planned milestones, it has become clear that our project would benefit from an even larger sample size. In particular, increasing sample sizes lead to exponential rather than linear increase in the number of loci identified. Moreover, in the past four years there has been tremendous technological advances in behavioral and genetic analysis that can be leveraged to provide unprecedented access to identify the single nucleotide and structural variants that contribute to complex behavioral endophenotypes of high relevance to cocaine use-disorders. The first goal of this competing renewal is to double the sample size of the current GWAS to increase the number of gene variants identified and meet the demands of the Biobank. The second goal is to use high-throughput behavioral phenotyping using markerless pose estimation based on transfer learning with deep neural network to identify behavioral endophenotypes that can help predict and identify individuals with a resistant, mild, moderate, or severe phenotype of cocaine addiction-like behaviors. The third goal is to use methodological improvements of the genetic analysis, including the analysis of structural variants and tandem repeats, as well as enhanced integration with gene expression data. The fourth goal is to strengthen the cocaine biobank infrastructure. This project is likely to continue having a sustained and powerful impact on the field because it will provide an exponential increase in the number of genetic loci identified, eQTLs and PheWAS analysis related to addiction- like behavior; establish the first high-throughput behavioral motifs analysis of addiction-like behaviors using parallel video-recording and automated machine learning analysis; identify novel behavioral endophenotypes of vulnerability/resistance to addiction-like behaviors; and expand and improve the Cocaine Biobank offering and infrastructure.

摘要