Fundamental Mechanisms of Higher-Order Circadian Rhythms

高阶昼夜节律的基本机制

• 批准号: 10713148
• 负责人: Kevin B Koronowski
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713148
• 关键词: Anatomy; Area; Behavior; Biochemical; Brain; Cell model; Cells; Circadian Dysregulation; Circadian Rhythms; Circulation; Complex; Coupled; Cues; Dedications; Disease; Environment; Fasting; Genetic; Goals; Health; Hepatocyte; Human; Human body; Individual; Knowledge; Life; Link; Liver; Mediator; Mentors; Methodology; Modernization; Molecular; Molecular Target; Organ; Organism; Periodicity; Peripheral; Physiological; Postdoctoral Fellow; Research; Skeletal Muscle; Societies; Testing; Time; Tissues; Training; Work; bioinformatics tool; circadian; circadian biology; circadian pacemaker; disorder risk; effective therapy; feeding; graduate student; in vivo; insight; molecular clock; mouse model; novel; programs; synergism

Abstract: Circadian clocks are a defining feature of living organisms. Rhythms originate from the molecular clocks of cells and propagate anatomically across the brain and body. A molecular understanding of the cooperation among 30 trillion individual clocks in the human body is a daunting yet important scientific challenge. Currently, much less is known of non-brain cell clocks, termed ‘peripheral clocks’ or ‘peripheral oscillators’. My research program aims to identify coordination mechanisms that enable higher-order (e.g., from cells to tissue) circadian rhythms and their physiological implications. To study clock function at the multi-oscillator level, we use molecular approaches and genetically defined cell and mouse models. We aim to achieve two goals specifically for this ESI MIRA R35 proposal. First, we will investigate how noisy, damped, and incomplete clock mechanisms within single cells combine to produce unified, precise, and robust rhythms at the organ-level. We will tease apart this coordination mechanism by applying single-cell methodologies and bioinformatic tools to quantify the behavior of individual hepatocyte oscillators under different liver rhythmicity states in vivo. Second, we will interrogate how rhythms are coupled across two peripheral organs. It is unclear how multiple tissue clocks synergize towards systemic-level control of daily homeostatic functions. Using a novel genetic mouse model that I have already constructed and validated, we will test the reciprocal influence between liver and skeletal muscle clocks and delineate the contribution of this axis to the biochemical makeup of the systemic circulation over circadian time. We will also determine how this axis is augmented by feeding-fasting behavior, a major brain-driven circadian cue. For both goals, we will focus on the identification of key molecular mediators and downstream homeostatic functions. The MIRA will afford us the ability to chase down the most impactful leads from these two areas and will allow me to dedicate more time to mentoring activities, an aspect of academic life that I am passionate about. My research program, based in circadian biology, provides a technically and conceptually rich training environment for graduate students and postdoctoral associates. As a whole, the proposed work will generate foundational knowledge of the complex inter-cellular interactions that generate rhythms. This knowledge is crucial for elucidating the molecular basis of rhythm disruption, an ever-growing occurrence in modern society. Circadian disruption is broadly linked with disease and thus understanding fundamental clock mechanisms offers insight into root causes of many human ailments. Likewise, the proposed studies will yield novel molecular targets aimed at counteracting rhythm disruption.

摘要： 生物钟是生物体的一个重要特征。节奏起源于分子钟 并在解剖学上在大脑和身体中传播。从分子上理解 在人体内30万亿个独立的时钟之间进行比对是一项艰巨而重要的科学挑战。目前， 对非脑细胞时钟的了解要少得多，称为“外围时钟”或“外围时钟”。我的研究 该计划旨在确定能够实现更高阶（例如，从细胞到组织）昼夜节律 节奏及其生理意义。为了在多振子水平上研究时钟函数，我们使用分子 方法和遗传定义的细胞和小鼠模型。我们的目标是实现两个目标， ESI MIRA R35提案。首先，我们将研究如何嘈杂，阻尼，和不完整的时钟机制， 单个细胞联合收割机在器官水平上产生统一、精确和强健的节奏。我们会把这个 通过应用单细胞方法和生物信息学工具来量化行为， 在不同的肝脏节律状态下，在体内的单个肝细胞振荡器。第二，我们将询问如何 节律通过两个外周器官耦合。目前还不清楚多个组织时钟如何协同作用， 日常自我平衡功能的系统水平控制。使用一种新的遗传小鼠模型，我已经 构建和验证，我们将测试肝脏和骨骼肌时钟之间的相互影响， 描绘该轴在昼夜节律时间内对体循环的生化组成的贡献。 我们还将确定这个轴是如何通过喂养-禁食行为来增强的，这是一种主要的大脑驱动的昼夜节律 球杆.对于这两个目标，我们将集中在确定关键的分子介质和下游稳态 功能协调发展的MIRA将为我们提供从这两个领域追逐最有影响力的线索的能力， 这将使我有更多的时间投入到指导活动中，这是我热爱的学术生活的一个方面。 我的研究计划，基于昼夜节律生物学，提供了一个技术和概念丰富的培训 为研究生和博士后提供良好的环境。总的来说，拟议的工作将产生 对产生节律的复杂细胞间相互作用的基础知识。这种知识是 这对于阐明现代社会中日益增长的节律紊乱的分子基础至关重要。 昼夜节律紊乱与疾病有着广泛的联系，因此了解基本的生物钟机制可以提供 深入了解许多人类疾病的根本原因。同样，所提出的研究将产生新的分子 旨在抵消节律紊乱的目标。