Circadian regulation of neuroprotective genes during aging

 描述（由申请人提供）：生物钟是细胞功能和体内平衡的重要调节因子。人类昼夜节律系统中的神经元相关改变与神经元病理学有关。最近在果蝇和小鼠中的证据表明，节律紊乱和神经退行性变之间存在相关性;然而，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比较了年轻和年老果蝇头部的昼夜节律转录组。正如预期的那样，我们发现在年轻果蝇中有节奏地表达的几个基因失去了它们的循环模式，在老年果蝇中变得组成性低或高。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较低，但在老年果蝇中表达较高，并且具有强烈的节律性。这一组包含已知的应激反应基因，这些基因在氧化应激或缺氧反应中被诱导，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协调神经保护基因的节律性表达，我们称之为晚期生命周期因子（LLC），以响应老化神经系统的内在压力和损伤。我们将在两个目标中检验我们的假设。在目标1中，我们将对年轻和老年男性和女性头部的昼夜节律转录组进行全面比较，以充分表征核心时钟和时钟控制基因中与年龄相关的变化，并确定这些变化是否具有性二态性。我们还将测试LLC节律是否在恒定的黑暗中保持，但在核心昼夜节律基因中具有时钟破坏无效突变的果蝇中被废除。在目标2中，我们将通过比较野生型和时钟突变型果蝇中存在或不存在LLC节律的衰老生物标志物来测试LLC是否发挥神经保护作用。我们还将测试是否暴露于外源性氧化应激诱导节律性LLC表达的年轻苍蝇。这个探索性的提议可能会揭示保护大脑免受年龄相关损伤的时钟控制通路。鉴于生物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。

 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.