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Investigation of the spontaneous circadian hamster mutation Theta

仓鼠自发昼夜节律突变 Theta 的研究

基本信息

批准号：
8784448
负责人：
Clark Jeffrey Rosensweig
金额：
$ 3.04万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-01 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8784448
关键词：
Address Adverse effects Affect Alleles Animal Model Animals Binding Biological Assay Cell Line Cells Cellular Assay Circadian Rhythms Data Data Set E-Box Elements Elements Feedback Fibroblasts Gene Family Genes Genetic Genetic Polymorphism Genetic Screening Genetic Transcription Genome Genomics Hamsters Health Hypothalamic structure Immunology Indium Investigation Light Mammals Maps Measures Mesocricetus auratus Messenger RNA Metabolism Molecular Mood Disorders Moods Mutation Obesity Open Reading Frames Peripheral Phase Phenotype Physiological Physiology Population Process Protein Dynamics Proteins Reporter Research Rivers Role Running Signal Transduction Site Sleep Societies Structure System Techniques Time Tissues Translations Variant Writing base casein kinase I critical period cryptochrome deep sequencing genome sequencing immune function insight luminescence mRNA Expression mutant next generation sequencing novel prevent protein expression public health relevance segregation suprachiasmatic nucleus trait transcription factor

项目摘要

DESCRIPTION (provided by applicant): A cell autonomous molecular clock temporally organizes many essential physiological functions. Disruption of the clock thus has numerous consequences for health. Forward genetic screens have identified multiple clock components and the core principles of the clock are highly conserved. Recently, our collaborator discovered a golden hamster (Mesocricetus auratus) with a spontaneous mutation (Theta) that results in a dramatic elongation of the hamster's endogenous period. The focus of this proposal will be to elucidate how this mutation disrupts known relationships between core clock genes and, eventually, to identify the mutation in the hamster genome. I will look at mRNA and protein expression dynamics in tissue to identify alterations in the relationships between known clock genes. To determine whether period elongation is a cell autonomous feature of the Theta clock, I will use cell-based real time luminescence reporters in primary fibroblast cultures. Finally, using whole genome sequencing and bulk segregation analysis, I will identify a candidate region in the hamster genome and narrow the field of variants through cellular assays until the causative mutation has been determined. Ultimately, Theta will provide insight into the mechanisms governing the correct timing of the endogenous clock.

描述(申请人提供)：一个细胞自主分子时钟暂时组织许多基本的生理功能。因此，生物钟的扰乱对健康造成了许多后果。正向遗传筛选已经确定了多个时钟成分，并且时钟的核心原理高度保守。最近，我们的合作者发现了一只金黄地鼠(Mesocricus Auratus)，它具有自发突变(Theta)，导致金黄地鼠的内生期显著延长。这项提议的重点将是阐明这种突变如何扰乱核心时钟基因之间的已知关系，并最终确定仓鼠基因组中的突变。我将观察组织中的mRNA和蛋白质表达动态，以确定已知时钟基因之间关系的变化。为了确定周期延长是否是Theta时钟的细胞自主特征，我将在原代成纤维细胞培养中使用基于细胞的实时发光报告。最后，使用全基因组测序和整体分离分析，我将在仓鼠基因组中确定一个候选区域，并通过细胞分析缩小变异范围，直到确定导致突变的原因。最终，Theta将提供对控制内源性时钟正确计时的机制的洞察。