Consequences of Circadian Desynchrony

昼夜节律不同步的后果

基本信息

批准号：
8878263
负责人：
DAVID Raymond WEAVER
金额：
$ 20.98万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
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：
2014-07-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8878263
关键词：
Address Alleles Animals Back Behavioral Biological Clocks Biology Bioluminescence Body Composition Brain Cardiovascular Diseases Casein Kinase Iepsilon Cells Chronic Circadian Rhythms Data Development Diet Disease Environment Fatty acid glycerol esters Gastrointestinal Diseases Gene Expression Genes Genotype Glucose Health Heart Hour Hypothalamic structure Incidence Individual Intervention Jet Lag Syndrome Kidney Lead Length Light Lighting Literature Malignant Neoplasms Mammals Melatonin Mental Depression Metabolic Metabolism Modeling Morbidity - disease rate Mus Mutant Strains Mice Nature Obesity Organism Outcome Pathology Periodicity Peripheral Phase Physiological Population Predisposition Process Relative (related person)Running Stress System Testing Time Tissues adverse outcome age related base brain tissue casein kinase I circadian pacemaker cost genetic manipulation in vivo insulin sensitivity light effects mouse model public health relevance research study response shift work theories

项目摘要

DESCRIPTION (provided by applicant): Shift work is associated with an increased incidence of numerous adverse health outcomes. These pathological responses are thought to result from the continual "stress" of re-setting the hypothalamic circadian pacemaker to the environment, the continual "stress" of re-setting clocks in peripheral tissues to the hypothalamic clock, or both. We recently developed mouse lines with conditional alleles of two casein kinase 1 (CK1) genes, CK1 delta and CK1 epsilon. These genes can be disrupted in a tissue-specific manner. Mice and tissues with disruption of most combinations of these conditional alleles have modest alterations in circadian cycle length (period), but mice, cells and tissues with disruption of both alleles of CK1delta and one allele of CK1 epsilon have a ~ 3-hour lengthening of circadian period. Notably, brain-specific disruption of these three CK1 alleles leads to mice with a brain clock running at ~27-hr per day, and a periphery that is normal (period length near 24 hr). We have assembled a team with diverse expertise to investigate the costs of circadian desynchrony in these mutant mice. Our overall hypothesis is that circadian desynchrony will lead to adverse consequences for health. The overall objective of our proposed studies is to assess whether circadian desynchrony, produced by genetic manipulation of the brain, leads to adverse health consequences. We will first assess rhythms in peripheral tissues and brain to assess their level of coordination in mice of different genotypes following tissue-specific gene disruption. We will then assess the pathophysiological impact of these altered temporal relationships. Based on prior literature, we will focus on metabolic responses (glucose handling and insulin sensitivity, body composition, susceptibility to diet-induced obesity), and histopathological changes in heart and kidney. Our studies will be the first to assess the importance of synchronization among circadian clocks without the potential confounding influence of repeatedly resetting the brain clock to a disruptive lighting cycle. We expect that loss of synchrony between circadian clocks throughout the body will have adverse consequences, even when the SCN clock is not faced with repeatedly re-setting. This finding would have important implications for pharmacological and non-invasive (light, behavioral, melatonin) strategies aimed at countering the adverse impact of shift work, as well as revealing important features of the hierarchical nature of the mammalian circadian timing system.

描述（由申请人提供）：轮班工作与许多不良健康结果的发生率增加有关。这些病理反应被认为是由将下丘脑昼夜节奏起搏器重新设置为环境的持续“应力”，在周围组织中重新设置时钟的连续“应力”，或两者兼有下丘脑。我们最近开发了小鼠系，具有两个酪蛋白激酶1（CK1）基因CK1 Delta和CK1 Epsilon的条件等位基因。这些基因可以以组织特异性的方式破坏。这些条件等位基因的大多数组合的小鼠和组织在昼夜节律的长度（周期）中都有适度的改变，但是小鼠，细胞和组织都会破坏CK1DELTA等位基因和一个CK1 Epsilon等位基因的昼夜节律时期约3小时。值得注意的是，这三个CK1等位基因的大脑特异性破坏导致小鼠每天约27小时的脑时钟，而外围是正常的（周期长度接近24小时）。我们已经组建了一个具有多种专业知识的团队，以调查这些突变小鼠中昼夜节律的成本。我们的总体假设是，昼夜节律将导致对健康的不利后果。我们提出的研究的总体目的是评估昼夜节律对大脑遗传操纵产生的昼夜节律是否会导致不利的健康后果。我们将首先评估周围组织和大脑中的节奏，以评估它们在组织特异性基因破坏后不同基因型小鼠中的配位水平。然后，我们将评估这些改变的时间关系的病理生理影响。基于先前的文献，我们将重点介绍代谢反应（葡萄糖处理和胰岛素敏感性，身体组成，对饮食诱导的肥胖症的敏感性）以及心脏和肾脏的组织病理学变化。我们的研究将是第一个评估昼夜节律之间同步重要性的重要性，而不会反复将大脑时钟重置为破坏性照明周期的潜在混淆影响。我们预计，即使没有反复重新设置SCN时钟，整个身体的昼夜节律之间的同步损失也会产生不利的后果。这一发现将对旨在抵消转移工作的不利影响的药理学和非侵入性（光，行为，褪黑激素）策略具有重要意义，并揭示了哺乳动物昼夜节律时间的层次性质的重要特征。