Circadian regulation of neuroprotective genes during aging
衰老过程中神经保护基因的昼夜节律调节
基本信息
- 批准号:9111180
- 负责人:
- 金额:$ 21.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-04-01 至 2018-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAgeAgingAging-Related ProcessAnimal ModelAnimalsBehavioralBioinformaticsBiologicalBiological MarkersBiology of AgingBrainCell physiologyCellsCircadian RhythmsCollaborationsComplementComputational BiologyDarknessDataDrosophila genusDrosophila melanogasterElderlyExposure toFemaleGene ExpressionGenesGeneticHeadHealthHeat shock factorHeat shock proteinsHomeostasisHumanHypoxiaIndividualKnowledgeLeadLearningLifeLightLinkLongevityMaintenanceMammalsMeasuresMemoryMolecularMusNerve DegenerationNervous system structureNeuronsOxidative StressPacemakersPathologyPathway interactionsPatternPeripheralPhysiological ProcessesPlayPredispositionProcessProteinsRNARegulationRoleScheduleStressSynaptic plasticitySystemTestingUp-RegulationWorkage effectage relatedaging brainbasecircadian pacemakerflygenome-wide analysishealthy aginginsightjuvenile animalmalemutantneuroprotectionnovelnull mutationpromoterpublic health relevanceresponsesexual dimorphismstress proteintranscriptometranscriptome sequencing
项目摘要
DESCRIPTION (provided by applicant): Circadian clocks are important regulators of cellular functions and homeostasis. Age-related alterations in the human circadian system are implicated in neuronal pathologies. Recent evidence in fruit flies and mice suggests a correlation between disrupted rhythms and neurodegeneration; however, very little is known about the mechanisms involved. To address this, we compared the circadian transcriptome in young and old Drosophila heads using RNA- Seq. As expected, we found that several genes that were expressed rhythmically in young flies lose their cycling patterns to become constitutively low or high in old flies. Surprisingly, we also uncovered a novel group of genes which were low and arrhythmic in heads of young flies that became highly expressed and strongly rhythmic in old. This group contains known stress- responsive genes that are induced in response to oxidative stress or hypoxia to protect proteins from damage. Based on our preliminary data, we hypothesize that the circadian system orchestrates rhythmic expression of neuroprotective genes, which we termed late life cyclers (LLCs), in response to intrinsic stress and damage in the aging nervous system. We will test our hypothesis in two Aims. In Aim 1, we will conduct a comprehensive comparison of the circadian transcriptome in the heads of young and old males and females to fully characterize age-related changes in core clock and clock-controlled genes, and determine whether these changes are sexually dimorphic. We will also test whether LLC rhythms are maintained in constant darkness but abolished in flies with clock-disrupting null mutations in core circadian genes. In Aim 2, we will test whether LLCs play neuroprotective roles by comparing biomarkers of aging in wild type and clock mutant flies with LLC rhythms present or absent. We will also test whether exposure to exogenous oxidative stress induces rhythmic LLC expression in young flies. This explorative proposal may reveal clock-controlled pathways that protect the brain from age-related damage. Given the conserved genetic mechanisms of the circadian clock and aging biology, these pathways may also function in mammals.
描述(由申请人提供):生物钟是细胞功能的重要调节者,而人类昼夜节律系统中与年龄相关的变化与神经元病理有关。然而,最近在果蝇和小鼠中的证据表明节律紊乱与神经变性之间存在相关性。为了解决这个问题,我们使用 RNA-Seq 比较了年轻和年老果蝇头部的昼夜节律转录组,结果正如预期的那样。令人惊讶的是,在年轻果蝇中有节律表达的几个基因失去了它们的循环模式,在年老果蝇中变得非常低或高,令人惊讶的是,我们还发现了一组新的基因,这些基因在年轻果蝇的头部中表达量低且无节律,但在这些基因中却变得高表达和高表达。该组包含已知的应激反应基因,这些基因是针对氧化应激或缺氧而诱导的,以保护蛋白质免受损伤。根据我们的初步数据,我们渴望昼夜节律系统能够协调有节奏的表达。我们将在目标 1 中对昼夜节律转录组进行全面比较,以应对衰老神经系统中的内在压力和损伤。我们还将测试 LLC 节律是否在持续黑暗中得以维持,但在夜间被废除。在目标 2 中,我们将通过比较野生型和存在或不存在 LLC 节律的时钟突变果蝇的衰老生物标志物来测试 LLC 是否发挥神经保护作用。考虑到生物钟和衰老生物学的保守遗传机制,外源性氧化应激会诱导幼果蝇有节律地表达 LLC。该途径也可能在哺乳动物中发挥作用。
项目成果
期刊论文数量(0)
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Jadwiga M Giebultowicz其他文献
Jadwiga M Giebultowicz的其他文献
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{{ truncateString('Jadwiga M Giebultowicz', 18)}}的其他基金
Exploring links between circadian clocks and aging.
探索生物钟与衰老之间的联系。
- 批准号:
8225201 - 财政年份:2011
- 资助金额:
$ 21.56万 - 项目类别:
Role of circadian clocks in maintaining a healthy nervous system
生物钟在维持神经系统健康中的作用
- 批准号:
8288704 - 财政年份:2011
- 资助金额:
$ 21.56万 - 项目类别:
Role of circadian clocks in maintaining a healthy nervous system
生物钟在维持神经系统健康中的作用
- 批准号:
8176952 - 财政年份:2011
- 资助金额:
$ 21.56万 - 项目类别:
Role of circadian clocks in maintaining a healthy nervous system
生物钟在维持神经系统健康中的作用
- 批准号:
8458655 - 财政年份:2011
- 资助金额:
$ 21.56万 - 项目类别:
Exploring links between circadian clocks and aging.
探索生物钟与衰老之间的联系。
- 批准号:
8030253 - 财政年份:2011
- 资助金额:
$ 21.56万 - 项目类别:
Exploring links between circadian clocks and aging.
探索生物钟与衰老之间的联系。
- 批准号:
8265501 - 财政年份:2011
- 资助金额:
$ 21.56万 - 项目类别:
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