Administrative supplement to MIRA proposal

MIRA 提案的行政补充

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10596846
• 关键词: Administrative Supplement; Architecture; Behavior; Binding Sites; Biochemical; Biochemistry; Biological; Biological Clocks; Cellular biology; Circadian Rhythms; Clock protein; Complex; Cues; Cyanobacterium; Funding; Genetic; Goals; Health; Hour; Human; Intervention; Lead; Light; Link; Mammals; Molecular; National Institute of General Medical Sciences; Pharmacology; Physiology; Post-Translational Protein Processing; Protein Dynamics; Proteins; Resources; Signal Transduction; System; Time; biophysical techniques; circadian; comparative; enzyme activity; flexibility; improved; insight; programs; protein function; structural biology; therapeutic development

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.

项目总结