Resolving the spatial dynamics of single cell circadian regulatory networks

解决单细胞昼夜节律调节网络的空间动态

• 批准号: 10676214
• 负责人: Kathleen M Greenham
• 金额: $ 37.84万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-03 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676214
• 关键词: Arabidopsis; Biological Models; Biological Process; Cardiometabolic Disease; Cells; Circadian Rhythms; Communication; Complex; Environment; Functional disorder; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Goals; Health; Human; Metabolic; Metabolism; Modeling; Molecular; Mouse-ear Cress; Neurodegenerative Disorders; Organ; Physiological; Physiological Processes; Plants; Power Plants; Regulator Genes; Research; Resolution; System; Time; Tissues; Variant; Whole Organism; Work; cardiometabolic risk; cell type; circadian; circadian pacemaker; circadian regulation; fitness; gene regulatory network; insight; model organism; network models; response; single cell technology; targeted treatment; trait

Project Summary/Abstract Physiological and metabolic health relies on the circadian alignment of biological processes with the environment. Since the first documented study of circadian rhythms in the 18th century using a plant system, model organisms have been critical for defining the transcriptional mechanism of the oscillator and revealing the importance of the clock on fitness. Most of this work is based on whole organism or organ level studies leaving many mechanistic questions about how cell specific gene regulation leads to coordination of cellular clocks and a concerted physiological response. We know that gene regulatory networks are effective at modeling gene expression dynamics but resolving cell-type specific networks with time resolution remains a significant challenge. To delineate regulatory connections across cell-types, a single cell view is needed to develop network models that reflect the true cell state rather than the variation among groups of cells or tissues. Only with these cell specific networks can we begin to develop testable hypotheses about what regulatory variation underlies physiological responses. This proposal describes a research strategy that leverages the genetic and molecular power of the plant model system Arabidopsis thaliana and the latest single cell technologies to 1) Identify the cell-types with distinct oscillators and their underlying regulatory networks, 2) Dissect how cell-type specific circadian regulatory networks maintain a synchronized physiological response, and 3) Perturb cell-type specific circadian gene regulatory networks and evaluate their physiological consequences. Over the next five years, our goals are to delineate single cell circadian gene regulatory networks across an entire organ with spatial resolution. Our Arabidopsis model system will be used to dissect how distinct cell type specific circadian regulation controls a physiological response. Through perturbations to tissue specific gene regulatory networks we will gain a better understanding of how cellular gene programming is coordinated. Our long-term goal is to develop Arabidopsis into a model for understanding how cell specific gene regulatory networks influence inter-tissue communication. This research will generate valuable insight into how we interpret the influence of circadian gene regulatory variation on human health and the application of targeted therapies.

项目总结/摘要 生理和代谢健康依赖于生物过程的昼夜节律调整， 环境自从世纪第一次使用植物系统对昼夜节律进行记录研究以来， 模式生物对于定义振荡器的转录机制和揭示 时钟对健康的重要性这项工作的大部分是基于整个生物体或器官水平的研究， 许多关于细胞特异性基因调控如何导致细胞时钟协调的机械问题， 协调一致的生理反应我们知道，基因调控网络是有效的建模基因 表达动力学，但用时间分辨率解析细胞类型特异性网络仍然是一个重要的问题。 挑战. 为了描绘跨细胞类型的调节连接，需要单个细胞视图来开发网络 反映真实细胞状态的模型，而不是细胞或组织组之间的变化。只有具备这 我们开始发展可检验的假说， 生理反应。该提案描述了一种利用遗传和分子生物学的研究策略， 植物模型系统拟南芥和最新的单细胞技术的力量，1）确定 具有不同振荡器的细胞类型及其潜在的调控网络，2）剖析细胞类型特异性 昼夜节律调节网络维持同步的生理反应，和3）干扰细胞类型特异性的 昼夜节律基因调控网络，并评估其生理后果。 在接下来的五年里，我们的目标是描绘单细胞昼夜节律基因调控网络， 一个具有空间分辨率的完整器官我们的拟南芥模型系统将用于解剖不同的细胞 类型特异性昼夜节律调节控制生理反应。通过对特定组织的扰动 基因调控网络，我们将获得更好地了解细胞基因编程是如何协调的。 我们的长期目标是将拟南芥发展成为一个模型，以了解细胞特异性基因调控 网络影响组织间通信。这项研究将产生有价值的见解，我们如何解释 昼夜节律基因调控变异对人类健康的影响及靶向治疗的应用。