Assessing Intertissue Communication in the Mammalian Circadian System

评估哺乳动物昼夜节律系统中的组织间通讯

• 批准号: 10315821
• 负责人: Dora Obodo
• 金额: $ 3.08万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10315821
• 关键词: Address; Affect; Automobile Driving; Behavior; Biological; Brain; Brain region; Cells; Chronic; Circadian Dysregulation; Circadian Rhythms; Circadian desynchrony; Collection; Communication; Complex; Cues; Data; Data Set; Disease; Drug Targeting; Eating; Endocrine; Ensure; Foundations; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genotype; Glucocorticoids; Goals; Health; Hormones; Hour; Human; Insulin; Jet Lag Syndrome; Life; Life Style; Lighting; Linear Models; Malignant Neoplasms; Maps; Mediating; Metabolic Diseases; Metabolism; Modernization; Molecular; Mus; Organ; Organism; Output; Pathway interactions; Periodicity; Peripheral; Phase; Physiology; Play; Property; Risk; Role; Series; Signal Pathway; Signal Transduction; Source; Statistical Methods; System; Temperature; Testing; Therapeutic Agents; Time; Tissues; Work; analytical method; circadian; circadian pacemaker; circadian regulation; computerized tools; design; drug development; experimental study; genome-wide; large scale data; loss of function; malignant breast neoplasm; novel; programs; receptor; response; shift work; suprachiasmatic nucleus; transcriptome

PROJECT SUMMARY/ABSTRACT Circadian rhythms are near 24-hour cycles in physiology that are fundamental to human health. Diseases such as breast cancer and other metabolic disorders are associated with circadian rhythm disruptions because of shiftwork, 24-hour lighting, chronic jet lag, and other factors of modern-day life. Circadian rhythms are created by endogenous molecular oscillators, or clocks, that regulate transcriptional rhythms. Communication between these clocks is integral to their function as a well-coordinated system. Despite their importance, circadian inter- tissue communication mechanisms are poorly understood and properties that govern circadian coordination are unknown. Yet, studies suggest that circulating endocrine factors, such as insulin and glucocorticoids, may play a role in synchronization as they can phase shift core genes of the clock machinery. Thus, the hypothesis is that endocrine pathways are sources of circadian inter-tissue communication and are affected by circadian misalignment and disruption. Defining factors of inter-tissue communication between clocks and characterizing temporal interactions in genome-scale data is critical to explain how tissues and organs orchestrate critical daily programs such as metabolism. To investigate circadian function and gene regulation, studies use complex time-series designs to manipulate clock genes and environmental conditions across one or multiple tissues. Yet, statistical and analytical methods do not reliably quantify rhythmic effects (amplitude and phase) nor interaction effects with conditions tested in such large-scale data. Yet, rhythmic properties such as amplitude and phase can fully describe a gene’s rhythm and change to that rhythm (differential rhythmicity) as a result of perturbation in complex experiments. The goal of this project is to identify factors of inter-tissue communication by addressing these statistical challenges to circadian gene expression analysis. I will build a statistical framework to estimate effects for amplitude and phase of genes in wild type experiments, as well as changes in amplitude and phase in experiments with two or more conditions (differential rhythmicity). Properly quantifying these properties will provide a detailed characterization of rhythmic features in genome-scale data. With these properties, I will leverage publicly available circadian transcriptome data to analyze phase similarities in signaling pathways between tissues and construct a map of potential inter-tissue signaling interactions across the day. This work will identify components that define relationships between tissue clocks at the gene expression level. These factors can be targeted as therapeutic agents for conditions caused by circadian disruption and dysregulation in our everyday life.

项目摘要/摘要 昼夜节律在生理学中接近24小时的周期，这是人类健康的基础。疾病 例如乳腺癌和其他代谢性疾病与昼夜节律中断有关 班次，24小时照明，慢性喷气滞后以及现代生活的其他因素。创造了昼夜节律 通过调节转录节奏的内源性分子振荡器或时钟。之间的沟通 这些时钟是它们作为协调良好系统的功能不可或缺的。尽管它们的重要性，但昼夜节律 组织通信机制知之甚少，控制昼夜节律协调的特性是 未知。然而，研究表明，循环内分泌因子（例如胰岛素和糖皮质激素）可能会发挥作用 在同步中的作用，因为它们可以相移的时钟机械基因。那是假设 内分泌途径是昼夜节律通讯的来源，受昼夜节律的影响 错位和破坏。定义时钟之间组织间通信的因素和表征 基因组规模数据中的临时相互作用对于解释组织和器官如何进行关键的每日关键 诸如新陈代谢的程序。 为了研究昼夜节律调节，研究使用复杂的时间序列设计 操纵时钟基因和一个或多次的环境条件。但是，统计和 分析方法不能可靠地量化有节奏效应（振幅和相），也不能可靠地与 在这样的大规模数据中测试的条件。然而，诸如放大器和相等有节奏的特性可以完全 描述一个基因的节奏，并改变了这种节奏（差异节奏）。 复杂的实验。 该项目的目的是通过解决这些统计数据来识别组织间沟通的因素 昼夜节律表达分析的挑战。我将建立一个统计框架来估计 野生型实验中基因的放大器和基因相，以及放大器和相位的变化 具有两个或多个条件的实验（差异节奏性）。正确量化这些属性将 提供基因组规模数据中节奏特征的详细表征。有了这些属性，我将 利用公开可用的昼夜节律转录组数据来分析信号通路中的相似性 在组织之间并构建全天潜在的组织间信号相互作用的图。这项工作 将确定定义基因表达水平组织时钟之间关系的组件。这些 因素可以作为因昼夜节律破坏和失调引起的治疗剂而定为治疗剂 我们的日常生活。