Assessing Intertissue Communication in the Mammalian Circadian System

项目摘要/摘要 昼夜节律是生理上的近24小时循环，对人类健康至关重要。疾病 如乳腺癌和其他代谢紊乱与昼夜节律紊乱有关，因为 轮班工作，24小时照明，慢性时差，以及现代生活的其他因素。昼夜节律是由 通过调节转录节奏的内源分子振荡器或时钟。相互之间的通信 这些时钟对于它们作为一个协调良好的系统的功能是不可或缺的。尽管它们很重要，但昼夜节律之间- 组织通讯机制知之甚少，支配昼夜协调的特性是 未知。然而，研究表明，循环中的内分泌因素，如胰岛素和糖皮质激素，可能起作用。 起到了同步的作用，因为它们可以相移时钟机械的核心基因。因此，假设是 内分泌通路是昼夜节律组织间通讯的来源，并受昼夜节律的影响 错位和破坏。时钟间组织间通信因素的定义和表征 基因组规模数据中的时间相互作用对于解释组织和器官如何协调关键的日常生活至关重要 新陈代谢等程序。 为了研究昼夜节律功能和基因调控，研究使用复杂的时间序列设计来 在一个或多个组织中操纵时钟基因和环境条件。然而，统计和 分析方法不能可靠地量化节律效应(幅度和相位)或相互作用的影响 在如此大规模的数据中测试的条件。然而，诸如幅度和相位之类的节奏属性可以完全 描述一个基因的节律以及该节律的变化(差异节律性)，其结果是 复杂的实验。 该项目目标是通过处理这些统计数据来确定组织间通信的因素 昼夜节律基因表达分析面临的挑战。我将建立一个统计框架来评估 野生型实验中基因的振幅和相位，以及 有两种或两种以上条件的实验(不同的节奏性)。适当地量化这些属性将 提供基因组规模数据中节律特征的详细表征。有了这些属性，我将 利用可公开获得的昼夜节律转录组数据来分析信号通路中的阶段相似性 并构建一张一天中潜在组织间信号相互作用的地图。这部作品 将确定在基因表达水平上定义组织时钟之间关系的组件。这些 因子可以作为治疗由昼夜节律紊乱和失调性疾病引起的疾病的药物。 我们的日常生活。

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.