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器。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。最近在果蝇和小鼠身上的证据表明，节律紊乱与神经退行性疾病之间存在相关性。然而，人们对所涉及的机制知之甚少。为了解决这个问题，我们使用 RNA 测序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律表达的几个基因失去了它们的循环模式，而在年老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，这些基因在幼果蝇的头部中表达量低且节律不齐，但在年老果蝇中表达量高且节律性强。该组包含已知的应激反应基因，这些基因是响应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，我们假设昼夜节律系统协调神经保护基因的节律表达，我们将其称为晚期生命周期（LLC），以应对衰老神经系统中的内在压力和损伤。我们将在两个目标中检验我们的假设。在目标1中，我们将对年轻和年老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的年龄相关变化，并确定这些变化是否具有性别二态性。我们还将测试 LLC 节律是否在持续黑暗中得以维持，但在核心昼夜节律基因中存在时钟干扰无效突变的果蝇中是否被废除。在目标 2 中，我们将通过比较野生型果蝇和存在或不存在 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。我们还将测试暴露于外源氧化应激是否会诱导幼果蝇有节奏的 LLC 表达。这一探索性提议可能揭示保护大脑免受年龄相关损伤的时钟控制途径。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发挥作用。

 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.