Administrative supplement to MIRA proposal

MIRA 提案的行政补充

基本信息

批准号：
10596846
负责人：
Carrie L Partch
金额：
$ 21.98万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA CRUZ
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2026-04-30
项目状态：
未结题

项目摘要

Project Summary Circadian rhythms arise from genetically encoded clocks that are intimately linked to external cues like light to synchronize physiology and behavior with the 24-hour solar cycle. Although the genetic networks that give rise to circadian rhythms are now relatively well established, we still don’t understand many of the fundamental, molecular steps that determine the ~24-hour basis of these clocks and how they respond to external time-setting cues. By integrating structural biology and solution biophysical methods with biochemistry and cell biology, we aim to determine the underlying biochemical principles that lead to the day-long timescale of circadian signaling and uncover the mechanisms that allow biological clocks to faithfully maintain intrinsic timing and respond robustly to external cues. With prior NIGMS funding, we studied clock systems from mammals and cyanobacteria to discover how different clock proteins assemble into regulatory complexes and identified how protein dynamics, enzyme activity and/or post-translational modifications impact clock timing. Our comparative biochemical approach highlighted surprising commonalities, such as the competition for mutually exclusive binding sites, between these clocks despite their different molecular architectures. Here, we will continue to pursue the structural basis of protein assemblies from diverse biological clocks, determine the consequences of post- translational modifications on clock protein function, study the molecular basis for entrainment of clocks to external cues, and seek out new inroads for pharmacological intervention. Funding from the MIRA program would provide us with the resources and flexibility to explore commonalities in mechanisms of biological timekeeping across a diverse array of species from cyanobacteria to humans.

项目概要昼夜节律源自基因编码的时钟，这些时钟与外部线索（例如光、光线）密切相关。尽管产生的遗传网络使生理和行为与 24 小时太阳周期同步。虽然昼夜节律现在已经相对完善，但我们仍然不了解许多基本原理，决定这些时钟的 24 小时基础以及它们如何响应外部时间设置的分子步骤通过将结构生物学和溶液生物物理方法与生物化学和细胞生物学相结合，我们旨在确定导致昼夜节律信号传导的一天时间尺度的基本生化原理并揭示生物钟忠实地维持内在计时和响应的机制在之前的 NIGMS 资助下，我们研究了哺乳动物和蓝细菌的时钟系统。发现不同的时钟蛋白如何组装成调节复合物并确定蛋白质动力学如何，酶活性和/或翻译后修饰影响时钟计时。方法强调了令人惊讶的共同点，例如相互排斥的结合位点的竞争，尽管这些时钟的分子结构不同，但在这里，我们将继续追求。来自不同生物钟的蛋白质组装的结构基础，确定后的后果对时钟蛋白功能的翻译修饰，研究时钟夹带的分子基础外部线索，并寻求 MIRA 项目资助的新进展。将为我们提供资源和灵活性来探索生物机制的共性从蓝细菌到人类的多种物种的计时。