Establishment and Characterization of Novel Mutant Mouse Models for the Addiction Research Community

成瘾研究界新型突变小鼠模型的建立和表征

• 批准号: 10647879
• 负责人: VIVEK KUMAR
• 金额: $ 82.41万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10647879
• 关键词: Acute; Animals; Anxiety; Behavior; Behavioral; Behavioral Assay; Biological; Biological Assay; Biology; Brain; Brain imaging; Brain region; Candidate Disease Gene; Child; Cocaine; Code; Collaborations; Communities; Complement; Corpus striatum structure; Darkness; Data; Data Set; Drug abuse; Economics; Emotional; Gene Deletion; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Genetic Models; Genetic Transcription; Genomics; Goals; Hippocampus; Hospitals; Human; Hyperactivity; Image; Impulsivity; Individual; Institution; Knock-out; Knockout Mice; Laboratories; Light; Link; Magnetic Resonance Imaging; Maps; Measurement; Measures; Medial; Mediating; Metabolism; Midbrain structure; Modeling; Mus; Neuroanatomy; Neurobiology; Neurons; Outcome; Pathway interactions; Pharmaceutical Preparations; Phenotype; Physiology; Prefrontal Cortex; Process; Proteins; Public Health; Publishing; Quantitative Trait Loci; Research; Resources; Rewards; Rodent; Seizures; Self Administration; Sleep; Structure; System; Systems Analysis; Tail Suspension; Testing; The Jackson Laboratory; Therapeutic Intervention; Therapeutic community technique; Tissues; Validation; Variant; Work; addiction; behavioral phenotyping; body system; brain reward regions; cocaine sensitization; cost; design; deviant; drug response prediction; effective therapy; experimental study; gene discovery; genetic resource; genetic variant; genome wide association study; image processing; in vivo; innovation; insight; knock out mouse project; knockout gene; loss of function; mesolimbic system; mouse genome; mouse model; mutant; mutant mouse model; neuron development; novel; novel therapeutics; pleiotropism; preference; prepulse inhibition; programs; psychostimulant; reverse genetics; scale up; social; therapeutic development; trait impulsivity; transcriptome; transcriptome sequencing; transcriptomics; virtual

PROJECT SUMMARY/ABSTRACT Addiction is an enormous economic, personal, and social burden, costing over $600 billion per year in the U.S. Understanding vulnerability to addiction, and developing effective therapies, requires identifying the genes and pathways that mediate the addiction process. Our long-term goal is to develop novel genetic models for addiction-relevant phenotypes, and use these models to characterize the genetic mechanisms of addiction. We propose to leverage the Jackson Laboratory Knockout Mouse Project 2 (JAX KOMP2) pipeline to prioritize addiction gene candidates, and then characterize the effects of candidate gene knockouts on addiction-related behaviors and on addiction-relevant tissues. The JAX KOMP2 Phenotyping Center performs high-throughput phenotyping of knockout mice across organ systems using an efficient, broad-based testing pipeline including behavioral assays for emotionality and sleep, both predictive of addiction phenotypes. Here we propose to exploit this rich KOMP2 dataset to select a subset of lines with emotionality and neuronal phenotypes (e.g. deviant open field, light dark, hole board, tail suspension, prepulse inhibition, rotarod, electroconvulsive seizure threshold, or sleep phenotypes) and lacking metabolism and physiology phenotypes. Our preliminary data provide compelling evidence that gene deletions leading to emotionality phenotypes in the KOMP pipeline have addiction phenotypes. We will subject these lines to deep drug abuse–relevant phenotyping, including drug self-administration, transcriptional profiling from key neuronal tissues, and whole brain imaging. The data from these will be integrated using systems analysis. The successful completion of this project will yield dozens of novel mouse models with detailed transcriptome, and neuroanatomical profile to establish mechanistic insight into this behavioral abnormality. These can serve are a resource for the research community for therapeutics development.

项目概要/摘要 成瘾是一种巨大的经济、个人和社会负担，在美国每年造成的损失超过 6000 亿美元。 了解成瘾的脆弱性并开发有效的治疗方法需要识别基因和 介导成瘾过程的途径。我们的长期目标是开发新的遗传模型 成瘾相关的表型，并使用这些模型来表征成瘾的遗传机制。我们 建议利用 Jackson Laboratory Knockout Mouse Project 2 (JAX KOMP2) 流程来确定优先级 成瘾基因候选，然后表征候选基因敲除对成瘾相关的影响 行为和成瘾相关组织。 JAX KOMP2 表型中心执行高通量 使用高效、广泛的测试流程对跨器官系统的基因敲除小鼠进行表型分析，包括 情绪和睡眠的行为分析，两者都可以预测成瘾表型。在此我们建议 利用这个丰富的 KOMP2 数据集来选择具有情感和神经元表型的品系子集（例如 异常开放视野、亮暗、孔板、尾悬吊、前脉冲抑制、旋转杆、电惊厥发作 阈值或睡眠表型）并且缺乏新陈代谢和生理学表型。我们的初步数据 提供令人信服的证据证明基因缺失会导致 KOMP 管道中的情绪表型 具有成瘾表型。我们将对这些品系进行深度药物滥用相关的表型分析，包括 药物自我给药、关键神经元组织的转录谱分析以及全脑成像。数据 这些将使用系统分析进行整合。该项目的顺利完成将产生数十 具有详细转录组和神经解剖学特征的新型小鼠模型，以建立机制 洞察这种行为异常。这些可以为研究界提供资源 治疗学的发展。

项目成果

Action detection using a neural network elucidates the genetics of mouse grooming behavior.

• DOI: 10.7554/elife.63207
• 发表时间: 2021-03-17
• 期刊: eLife
• 影响因子: 7.7
• 作者: Geuther BQ;Peer A;He H;Sabnis G;Philip VM;Kumar V
• 通讯作者: Kumar V

Stride-level analysis of mouse open field behavior using deep-learning-based pose estimation.

• DOI: 10.1016/j.celrep.2021.110231
• 发表时间: 2022-01-11
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Sheppard K;Gardin J;Sabnis GS;Peer A;Darrell M;Deats S;Geuther B;Lutz CM;Kumar V
• 通讯作者: Kumar V