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

项目摘要/摘要 上瘾是一个巨大的经济、个人和社会负担，在美国每年造成超过6000亿美元的损失。 了解上瘾的易感性，并开发有效的治疗方法，需要识别基因和 调节成瘾过程的途径。我们的长期目标是开发新的遗传模型 与成瘾相关的表型，并使用这些模型来表征成瘾的遗传机制。我们 建议利用杰克逊实验室基因敲除鼠标项目2(JAX KOMP2)管道来确定优先顺序 ，然后表征候选基因敲除对成瘾相关的影响 行为和与成瘾相关的组织。JAX KOMP2表型中心执行高通量 使用高效、基础广泛的测试管道跨器官系统对基因敲除小鼠进行表型鉴定，包括 情绪性和睡眠的行为分析，两者都可以预测成瘾的表型。在此，我们建议 利用这个丰富的KOMP2数据集来选择具有情绪性和神经元表型的线条子集(例如 异常开野、暗光、孔板、尾部悬吊、脉冲前抑制、旋转棒、电惊厥发作 阈值，或睡眠表型)，缺乏新陈代谢和生理表型。我们的初步数据 提供令人信服的证据表明基因缺失导致KOMP管道中的情绪性表型 有上瘾的表型。我们将对这些线路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图谱，以及全脑成像。数据 将使用系统分析将这些数据整合在一起。这个项目的成功完成将产生数十个 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 对这一行为异常的洞察。这些可以为研究社区提供资源 治疗学的发展。

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.