Understanding the Gene Regulatory Mechanisms That Underlie Age-Induced Changes in the Circadian System and Neurodegeneration

了解年龄引起的昼夜节律系统变化和神经退行性疾病背后的基因调控机制

• 批准号: 10404992
• 负责人: David Anthony Hendrix
• 金额: $ 36.14万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404992
• 关键词: ATAC-seq; Affect; Age; Age of Onset; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Animal Model; Automobile Driving; Autopsy; Behavior; Behavioral; Binding; Biological; Biological Markers; Biology of Aging; Brain; Cell physiology; ChIP-seq; Chromatin; Chronobiology; Circadian Dysregulation; Circadian Rhythms; Clinical Research; Computational Biology; Computer Models; DNA Binding; Data; Dementia; Disease; Drosophila genus; Elderly; Epigenetic Process; Erythroid; Event; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genome; Genomics; Head; Health; Heat shock factor; Homeostasis; Human; Hyperoxia; Hypoxia Inducible Factor; Individual; Knock-out; Lead; Life Cycle Stages; Longevity; Mammals; Measurement; Measures; MicroRNAs; Molecular; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurophysiology - biologic function; Nuclear; Output; Oxidative Stress; Pathology; Pathway interactions; Patients; Pattern; Periodicity; Persons; Phenocopy; Physiological Processes; Play; Post-Transcriptional Regulation; Predisposition; Publications; Publishing; RNA Interference; RNA Polymerase II; Regulator Genes; Rodent; Role; Sleep; Small RNA; Stress; System; Systems Biology; Testing; Time; Work; age related; age related neurodegeneration; base; biological adaptation to stress; circadian; circadian pacemaker; circadian transcriptome; combat; data modeling; flexibility; fly; follow-up; genetic manipulation; genome-wide; genomic data; healthy aging; heat shock transcription factor; in vivo evaluation; innovation; insight; kinetic model; network models; novel; overexpression; oxidative damage; pre-clinical; predictive modeling; prevent; promoter; response; tool; transcription factor; transcriptome; transcriptome sequencing

PROJECT SUMMARY: The circadian system is an important network hub coordinating cellular functions and homeostasis. Age-related alterations in the human circadian system are implicated in Alzheimer’s and other neuronal pathologies. Recent evidence in fruit flies and mice suggests correlation between disrupted rhythms and neurodegeneration; however, very little is known about mechanisms involved. To investigate these mechanisms, we compared circadian transcriptome in heads of young and old Drosophila using RNA-seq. We found that several genes, early-life cyclers (ELCs), that were expressed in young flies in a rhythmic fashion lose cycling pattern to become constitutively low or high in old flies. We also uncovered a group of genes, which we termed late life cyclers (LLCs), that were low and arrhythmic in heads of young flies but became strongly rhythmic in heads of old flies. This group contains known stress- responsive genes that are induced in young flies in response to oxidative stress or hyperoxia. Based on these findings from our recently published data, we hypothesize that the circadian system is rewired during aging through a combination of alterations in inputs from, and outputs to, stress-response pathways, and changes in post-transcriptional regulation by age-altered microRNA expression. Because of the connections between the circadian system and neurodegeneration, we expect some of these changes could be harmful for neuronal heath, and others could be part of a protective mechanism. In Aim 1, we will measure genome-wide binding of the core circadian transcription factors (TFs) CLK and CYC, stress responsive TFs, and RNA Polymerase II through ChIP-Seq and identify age-specific binding events that could be responsible for these regulatory changes. In addition, we will perform ATAC-seq to measure chromatin accessibility. In Aim 2, we will develop network models of gene regulation by combining this new data, along with our existing RNA-seq data and forthcoming small RNA-seq data. We will build computational models and analyze genomic data to create a mechanistic understanding of the epigenetic changes leading to the observed age-onset changes in diurnal expression patterns. By comparing the networks that we will build for young and old flies, we will be able to identify candidate regulators of aging, neurodegeneration (CRANs) that we will follow up on. In Aim 3, we will study the role of these CRANs in neuronal health, lifespan, and behavioral rhythms. We will use genetic manipulation to determine the causative gene regulatory events responsible for changes in health and neurodegeneration. The proposed work should reveal clock-controlled pathways that protect the brain from age-related damage, as well as examples of age-onset dysregulation of the clock network or connected pathways. Given the conserved molecular basis of circadian clock and aging biology, we expect these pathways will also function in humans. !

项目摘要： 昼夜节律系统是一个重要的网络中心，可协调细胞函数和 稳态。人类昼夜节律系统中与年龄相关的变化已在 阿尔茨海默氏症和其他神经元病理。果蝇和小鼠的最新证据表明 扰乱的节奏与神经退行性之间的相关性；但是，很少知道 关于涉及的机制。为了研究这些机制，我们比较了昼夜节律 使用RNA-Seq的年轻人和老年果蝇的头部转录组。我们发现有几个 基因，早期的自行车手（ELC），以节奏的方式以年轻的苍蝇表达 骑自行车的模式将变得始终如一或旧苍蝇高。我们还发现了一群 我们称之为后期骑自行车者（LLC）的基因，年轻的头部较低且心律不齐 苍蝇，但在旧苍蝇的头上变得强烈有节奏。该组包含已知的应力 - 响应于氧化应激或高氧响应年轻蝇中诱导的反应基因。 根据我们最近发布的数据的这些发现，我们假设昼夜节律 通过在衰老期间通过输入的变化和输出的组合，系统重新连接 到应力反应途径，以及通过改变年龄的转录后调节的变化 microRNA表达。因为昼夜节律与 神经变性，我们希望其中一些变化可能对神经元热有害，并且 其他人可能是受保护机制的一部分。在AIM 1中，我们将测量全基因组结合 核心昼夜节律转录因子（TFS）CLK和CYC，应力响应TF和RNA 聚合酶II通过CHIP-seq并确定可能是年龄特异性的结合事件 负责这些监管变化。此外，我们将执行ATAC-SEQ以测量 染色质可及性。在AIM 2中，我们将通过 结合这些新数据，以及我们现有的RNA-seq数据和即将推出的小RNA-seq 数据。我们将构建计算模型并分析基因组数据以创建机理 了解表观遗传变化，导致观察到的年龄变化 表达模式。通过比较我们将为年轻苍蝇建立的网络，我们将 能够识别我们将遵循的老化，神经退行性（Crans）的候选调节剂 之上。在AIM 3中，我们将研究这些启动在神经元健康，寿命和 行为节奏。我们将使用遗传操纵来确定病因基因 负责健康和神经退行性变化的监管事件。拟议的工作 也应该揭示钟表控制的途径，以保护大脑免受年龄相关损害的影响 作为时钟网络或连接途径的年龄发作失调的示例。鉴于 昼夜节律和衰老生物学的保守分子基础，我们希望这些途径将 还在人类中发挥作用。 呢

项目成果

Age-dependent effects of blue light exposure on lifespan, neurodegeneration, and mitochondria physiology in Drosophila melanogaster.

• DOI: 10.1038/s41514-022-00092-z
• 发表时间: 2022-07-27
• 期刊: NPJ AGING
• 作者: Song, Yujuan;Yang, Jun;Law, Alexander D;Hendrix, David A;Kretzschmar, Doris;Robinson, Matthew;Giebultowicz, Jadwiga M
• 通讯作者: Giebultowicz, Jadwiga M