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.

抽象的： 生物钟是生物体的一个决定性特征，节律源自分子钟。 细胞并在大脑和身体中进行解剖学传播。 目前，研究人体 30 万亿个个体时钟是一项艰巨但重要的科学挑战。 我的研究对非脑细胞时钟（称为“外周时钟”或“外周振荡器”）知之甚少。 该计划旨在确定能够实现更高阶（例如从细胞到组织）昼夜节律的协调机制 为了研究多振荡器水平的时钟功能，我们使用分子。 我们的目标是专门为此实现两个目标。 ESI MIRA R35 提案首先，我们将研究内部时钟机制的噪声、阻尼和不完整程度。 单细胞结合起来在器官水平上产生统一、精确和稳健的节律，我们将对此进行梳理。 通过应用单细胞方法和生物信息学工具来量化行为的协调机制 其次，我们将探讨体内不同肝节律状态下个体肝细胞振荡器的变化。 节律在两个外周器官之间耦合，目前尚不清楚多个组织时钟如何协同作用。 使用我已经拥有的新型基因小鼠模型对日常稳态功能进行系统水平的控制。 构建并验证后，我们将测试肝脏和骨骼肌时钟之间的相互影响， 描述该轴在昼夜节律时间内对体循环生化构成的贡献。 我们还将确定该轴如何通过禁食行为增强，这是一种主要的大脑驱动的昼夜节律 对于这两个目标，我们将重点关注关键分子介质和下游稳态的识别。 MIRA 将使我们能够从这两个领域追寻最具影响力的线索。 将使我能够投入更多时间进行指导活动，这是我热衷的学术生活的一个方面。 我的研究项目以昼夜节律生物学为基础，提供了技术和概念上丰富的培训 总体而言，拟议的工作将产生研究生和博士后的环境。 产生节律的复杂细胞间相互作用的基础知识。 对于阐明节律紊乱的分子基础至关重要，节律紊乱在现代社会中日益频繁发生。 昼夜节律紊乱与疾病广泛相关，因此了解基本的时钟机制可以提供帮助 同样，拟议的研究将产生新的分子。 旨在抵消节律紊乱的目标。