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： 昼夜节律是活生物体的定义特征。节奏起源于分子钟 细胞并在大脑和身体上解剖学传播。对合作的分子理解 在人体中的300万亿个单个时钟中，有一个令人生畏而又重要的科学挑战。现在， 对非脑细胞时钟的已知要少得多，称为“外围时钟”或“外围振荡器”。我的研究 计划旨在确定能够使高阶（例如，从细胞到组织）的协调机制 节奏及其身体含义。要在多振荡器水平上研究时钟功能，我们使用分子 接近和普遍定义的单元格和鼠标模型。我们旨在为此专门实现两个目标 Esi Mira R35提案。首先，我们将调查如何内部的噪声，诅咒和不完整的时钟机制 单细胞结合在器官级别产生统一，精确和鲁棒的节奏。我们会教这个 通过应用单细胞方法和生物信息学工具来量化行为，协调机制 在体内不同肝节奏状态下的单个肝细胞振荡器。其次，我们将审问如何 节奏在两个外围器官之间耦合。目前尚不清楚多个组织如何协同朝向 每日体内稳态功能的全身级别控制。使用我已经拥有的新型遗传鼠标模型 经过构建和验证，我们将测试肝脏和骨骼肌时钟之间的相互影响 描述了该轴对昼夜节时间在全身圆的生化构成的贡献。 我们还将确定如何通过喂食行为来增强该轴，这是一个主要的脑驱动昼夜节律 提示。对于这两个目标，我们将重点介绍关键分子介体和下游稳态的识别 功能。 Mira将使我们能够追逐这两个领域最有影响力的潜在客户， 将使我能够将更多的时间用于心理活动，这是我热衷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，在技术上和概念上提供了丰富的培训 研究生和博士后同事的环境。总体而言，拟议的工作将产生 对产生节奏的复杂细胞间相互作用的基础知识。这些知识是 对于阐明节奏破坏的分子基础至关重要，这在现代社会中不断增长。 昼夜节律的干扰与疾病广泛有关，因此了解基本时钟机制提供 深入了解许多人类疾病的根本原因。同样，提出的研究将产生新的分子 旨在抵消节奏破坏的目标。