Circadian regulation of neuroprotective genes during aging

 描述(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改变与神经元病理有关。最近在果蝇和老鼠身上的证据表明，节律紊乱与神经退化之间存在相关性；然而，人们对其中涉及的机制知之甚少。为了解决这个问题，我们使用RNA-Seq比较了幼龄和老年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表达的几个基因失去了它们的循环模式，在老年果蝇中变成了结构性的低或高。令人惊讶的是，我们还发现了一组新的基因，这些基因在幼龄果蝇的头部低表达和心律不齐，在老年果蝇头部变得高度表达和强烈节律。这一组包含已知的应激反应基因，这些基因在氧化应激或低氧反应中被诱导，以保护蛋白质免受损害。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性表达，我们称之为晚期生命周期因子(LLC)，以应对老化神经系统的内在应激和损伤。我们将在两个目标上检验我们的假设。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的比较，以全面描述核心时钟和时钟控制基因随年龄的变化，并确定这些变化是否是性二态的。我们还将测试在核心昼夜节律基因发生时钟扰乱零突变的果蝇中，LLC节律是否保持在持续的黑暗中，但却被取消。在目标2中，我们将通过比较野生型和时钟突变果蝇的衰老生物标志物与LLC节律的存在或不存在来测试LLC是否起到神经保护作用。我们还将测试暴露在外源性氧化应激下是否会诱导幼蝇体内有节律性的LLC表达。这一探索性的建议可能揭示时钟控制的通路，保护大脑免受与年龄相关的损伤。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.