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.

抽象的 NIDA动物遗传学计划的目的是确定遗传，基因组，表观遗传变异， 有助于类似成瘾行为的生理和大脑功能，相关的行为内表型， 和对药物使用障碍的行为合并症。在过去的四年中，我们的多学科和 高度协作的财团一直在识别与增加有关的基因变体 通过使用高级慢性模型执行第一个GWA的脆弱性使用强迫性可卡因的使用 N/NIH异质股（HS）中的静脉可卡因自我给药。我们还创建了第一个 临床前可卡因生物库，使没有资源的研究人员可以执行慢性 静脉自我给药或下一代基因组测序以执行晚期遗传， 分子和细胞研究，以进一步了解类似成瘾的生物学变化 行为。尽管这些努力在实现计划中的里程碑方面非常成功，但它已经成为 很明显，我们的项目将受益于更大的样本量。特别是，增加样本量的铅 指数级而不是线性增加的基因座数量。而且，在过去的四年中 在行为和遗传分析方面已经取得了巨大的技术进步，可以利用 提供前所未有的访问来识别有助于 与可卡因使用疾病高相关的复杂行为内表型。这个目标的第一个目标 竞争的更新是将当前GWA的样本量增加一倍，以增加基因变体的数量 确定并满足生物库的需求。第二个目标是使用高通量行为 使用基于转移学习的无标记姿势估算的表型和深度神经网络来识别 行为内表型可以帮助预测和识别具有抗性，轻度，中或 可卡因成瘾行为的严重表型。第三个目标是使用方法论改进 遗传分析，包括对结构变体和串联重复的分析，以及增强 与基因表达数据集成。第四个目标是加强可卡因生物库基础设施。这 项目可能会继续对该领域产生持续和强大的影响，因为它将提供 与成瘾有关的遗传基因座，EQTL和PHEWAS分析的指数增加 喜欢行为；使用使用的第一个高通量行为基序分析对成瘾行为进行分析 并行视频记录和自动化机器学习分析；识别新型的行为内表型 脆弱/抵抗类似成瘾的行为；扩展和改善可卡因生物库的产品 和基础设施。