Assessing Intertissue Communication in the Mammalian Circadian System

项目总结/摘要 昼夜节律是生理学中接近24小时的周期，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， 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 通过内源性分子振荡器，或时钟，调节转录节奏。之间的通信 这些时钟对于它们作为良好协调的系统的功能是不可或缺的。尽管它们的重要性，昼夜节律间- 组织通讯机制知之甚少，控制昼夜节律协调的特性 未知然而，研究表明，循环内分泌因子，如胰岛素和糖皮质激素，可能发挥作用， 在同步中的作用，因为它们可以相移时钟机制的核心基因。因此，假设是 内分泌途径是昼夜节律组织间通讯的来源， 错位和破坏。定义时钟之间的组织间通信的因素并表征 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重要的日常活动至关重要。 比如新陈代谢。 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， 在一个或多个组织中操纵生物钟基因和环境条件。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），也不能量化与 在如此大规模的数据测试条件。然而，节奏特性，如幅度和相位， 描述一个基因的节奏和节奏的变化（差异节奏性）作为扰动的结果， 复杂的实验 该项目的目标是通过解决这些统计问题来确定组织间通信的因素。 对昼夜节律基因表达分析的挑战。我将建立一个统计框架来估计 野生型实验中基因的振幅和相位，以及野生型实验中基因的振幅和相位的变化。 两个或两个以上条件的实验（差异节律性）。正确地量化这些属性将 提供基因组规模数据中节奏特征的详细表征。有了这些财产，我将 利用公开的昼夜节律转录组数据分析信号通路中的相位相似性 并构建一天中潜在的组织间信号相互作用的地图。这项工作 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 因子可以作为治疗剂靶向治疗由昼夜节律破坏和失调引起的病症， 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.