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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要成瘾是一种巨大的经济，个人和社会伯恩，在美国每年耗资超过6000亿美元了解成瘾和开发有效疗法的脆弱性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。我们提议利用杰克逊实验室淘汰鼠标项目2（JAX KOMP2）管道优先级成瘾基因候选者，然后表征候选基因敲除对成瘾有关的影响行为和与成瘾相关的时机。 JAX KOMP2表型中心执行高通量使用高效，基于广泛的测试管道（包括）包括情绪和睡眠的行为分析，都可以预测成瘾表型。在这里我们建议利用这个丰富的KOMP2数据集选择具有情感性和神经元表型的线的子集（例如偏离的开放田，浅色，孔板，尾悬架，预脉冲抑制作用，rotarod，电击癫痫发作阈值或睡眠表型），缺乏代谢和生理表型。我们的初步数据提供令人信服的证据表明，基因删除导致Komp管道中情绪表型的基因添加了表型。我们将使这些线深深滥用药物滥用 - 包括药物自我给药，关键神经组织的转录分析以及整个大脑成像。数据这些将使用系统分析整合。该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谱的新型小鼠模型以建立机械洞悉这种行为异常。这些可以服务是研究界的资源治疗性开发。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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