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：
Jadwiga M Giebultowicz
金额：
$ 21.56万
依托单位：
OREGON STATE UNIVERSITY
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：
https://reporter.nih.gov/project-details/9111180
关键词：
Address Affect Age Aging Aging-Related Process Animal Model Animals Behavioral Bioinformatics Biological Biological Markers Biology of Aging Brain Cell physiology Cells Circadian Rhythms Collaborations Complement Computational Biology Darkness Data Drosophila genus Drosophila melanogaster Elderly Exposure to Female Gene Expression Genes Genetic Head Health Heat shock factor Heat shock proteins Homeostasis Human Hypoxia Individual Knowledge Lead Learning Life Light Link Longevity Maintenance Mammals Measures Memory Molecular Mus Nerve Degeneration Nervous system structure Neurons Oxidative Stress Pacemakers Pathology Pathway interactions Pattern Peripheral Physiological Processes Play Predisposition Process Proteins RNA Regulation Role Schedule Stress Synaptic plasticity System Testing Up-Regulation Work age effect age related aging brain base circadian pacemaker fly genome-wide analysis healthy aging insight juvenile animal male mutant neuroprotection novel null mutation promoter public health relevance response sexual dimorphism stress protein transcriptome transcriptome 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（由适用提供）：昼夜节律是细胞功能和稳态的重要调节因子。人类昼夜节律系统中与年龄相关的改变是在神经元病理中实施的。水果蝇和小鼠的最新证据表明，节奏和神经退行性之间存在相关性。但是，对所涉及的机制知之甚少。为了解决这个问题，我们使用RNA-Seq比较了年轻和老年果蝇头的昼夜节律转录组。正如预期的那样，我们发现，在逻辑上以年轻苍蝇的逻辑表达的几个基因失去了骑自行车模式，以至于始终如一或旧苍蝇高或高。令人惊讶的是，我们还发现了一个新颖的基因，这些基因在年轻的苍蝇的头部较低且心律不齐，这些基因在旧的苍蝇中变得高度表达和强烈的节奏。该组包含已知的应激反应基因，这些基因响应氧化应激或缺氧，以保护蛋白质免受损伤。基于我们的初步数据，我们假设昼夜节律系统依赖神经保护基因的节奏表达，我们称它们为后期生命周期器（LLC），以响应衰老神经系统的内在压力和损害。我们将以两个目标来检验我们的假设。在AIM 1中，我们将对年轻男性和女性的昼夜节律转录组进行全面比较，以完全表征与年龄相关的核心时钟和时钟控制基因的变化，并确定这些变化是否是性二态性的。我们还将测试LLC节奏是否保持在恒定的黑暗中，但在核心昼夜节律基因中的苍蝇中废除了果蝇。在AIM 2中，我们将通过将野生型和时钟突变体衰老的生物标志物与存在或不存在的LLC节律进行比较，测试LLC是否扮演神经保护作用。我们还将测试暴露于外源氧化应激是否诱导幼体中的节奏有限责任公司的表达。该探索的提案可能揭示了可控制大脑免受年龄相关损害的时钟控制途径。鉴于昼夜节律时钟和衰老生物学的保守遗传机制，这些途径也可能在哺乳动物中起作用。