Identifying circadian rhythm genes from mouse mutants

鉴定小鼠突变体的昼夜节律基因

基本信息

批准号：
8149934
负责人：
JOSEPH S TAKAHASHI
金额：
$ 35.69万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2012-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8149934
关键词：
Behavior Behavioral Biochemical Biological Assay Candidate Disease Gene Casein Kinase Iepsilon Chromosome Mapping Chromosomes Circadian Rhythms Communities Darkness Deletion Mutation Drosophila genus ES Cell Line Electronic Mail Electroretinography Elements Ethylnitrosourea Feedback Functional Imaging Genes Genetic Genetic Polymorphism Genetic Screening Genome Genotype Haplotypes Histology Hour Inbred Strains Mice Knockout Mice Learning Length Lesion Light Mammals Maps Measurable Memory Molecular Mus Mutagenesis Mutant Strains Mice Mutation Nervous system structure Open Reading Frames Pathway interactions Phase Phenotype Play Positioning Attribute Reading Frames Research Research Personnel Resolution Resources Retinal Role Running SNP genotyping Stress System Testing Universities Vision Visual Visual Acuity Visual system structure circadian pacemaker ethylurea functional genomics gene discovery insight mouse genome mutant novel null mutation programs psychostimulant research study suprachiasmatic nucleus tool

项目摘要

DESCRIPTION (provided by applicant): Over the past decade, tremendous progress has been made in our understanding of the molecular mechanism of circadian clocks in mammals. Circadian oscillations are generated by a set of genes that form a transcriptional autoregulatory feedback loop. In mammals, there are at least seven different genes that have been proposed as 'core' circadian elements of the clock mechanism. Despite this remarkable progress, it is clear that a significant number of genes that regulate circadian rhythms in mammals remain to be discovered and identified. Forward genetic screens have been the most effective tool for circadian gene discovery, and we have used this approach to screen the mouse genome for circadian rhythm mutants in the Neurogenomics Project in the Center for Functional Genomics at Northwestern University. Over 60 new circadian mutants were identified as part of a large-scale ENU mutagenesis screen to create a mutant mouse resource for nervous system and behavioral phenotypes. Our specific aims are: 1. To identify the gene responsible for the 'Overtime' circadian period mutant in mouse. We will test the hypothesis that the 'Overtime' mutant represents a novel circadian rhythm gene. 2. To determine the genetic map position of twenty of the most robust circadian mutants isolated in our large- scale mutagenesis screen. To provide a more valuable research tool for the circadian research community, we propose to map 20 new circadian mutants. 3. To characterize and identify the 'swing-shift' mutant which is a novel entrainment mutant in mice. We will clone the 'swing-shift' mutant and test the hypothesis that 'swing-shift' mice have either a molecular or an anatomical lesion in the photic input pathway into the suprachiasmatic nucleus. Characterization of these novel circadian mutants and the identification of the causative genes should provide new insight into the mechanism of the mammalian circadian clock.

描述（由申请人提供）：在过去的十年中，在我们对哺乳动物昼夜节律钟的分子机制的理解中取得了巨大进步。昼夜节律振荡是由形成转录自动调节反馈回路的一组基因产生的。在哺乳动物中，至少有七个不同的基因被认为是时钟机制的“核心”昼夜节律元素。尽管取得了显着的进展，但很明显，在哺乳动物中调节昼夜节律的大量基因仍有待发现和鉴定。正向遗传筛选是昼夜节律发现的最有效的工具，我们已经使用这种方法在西北大学的功能基因组学中心的神经基因组学项目中筛选了昼夜节律节奏突变体的小鼠基因组。超过60个新的昼夜节律突变体被确定为大规模ENU诱变筛查的一部分，以创建一种用于神经系统和行为表型的突变小鼠资源。我们的具体目的是：1。确定小鼠中“加班”昼夜节律突变体的基因。我们将检验以下假设：“加班”突变体代表了一种新颖的昼夜节律基因。 2。确定在我们的大规模诱变筛选中分离的二十个最健壮的昼夜节律突变体的遗传图位置。为了为昼夜节律研究社区提供更有价值的研究工具，我们建议绘制20个新的昼夜节律突变体。 3。要表征和识别“摇摆档”突变体，这是小鼠中一种新颖的夹带突变体。我们将克隆“挥杆换档”突变体，并检验“挥杆换档”小鼠在光学输入途径中具有分子或解剖病变的假说，进入上核核。这些新型昼夜节律突变体的表征和因果基因的鉴定应提供对哺乳动物昼夜节律时钟机制的新见解。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Central and peripheral circadian clocks in mammals.

DOI：
10.1146/annurev-neuro-060909-153128
发表时间：
2012
期刊：
Annual review of neuroscience
影响因子：
13.9
作者：
Mohawk JA;Green CB;Takahashi JS
通讯作者：
Takahashi JS

Neuromedin s-producing neurons act as essential pacemakers in the suprachiasmatic nucleus to couple clock neurons and dictate circadian rhythms.

DOI：
10.1016/j.neuron.2015.02.006
发表时间：
2015-03-04
期刊：
Neuron
影响因子：
16.2
作者：
Lee IT;Chang AS;Manandhar M;Shan Y;Fan J;Izumo M;Ikeda Y;Motoike T;Dixon S;Seinfeld JE;Takahashi JS;Yanagisawa M
通讯作者：
Yanagisawa M

Molecular architecture of the mammalian circadian clock.