Exploring the structural basis for 24-hour timekeeping in mammals

探索哺乳动物 24 小时计时的结构基础

基本信息

批准号：
8557176
负责人：
Carrie L Partch
金额：
$ 28.28万
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：
2013
资助国家：
美国
起止时间：
2013-08-15 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8557176
关键词：
Address Affect Basic Science Behavior Binding Binding Sites Biochemical Biochemical Process Biochemistry Biological Process Biology C-terminal Cardiovascular Diseases Cell Proliferation Cells Cellular biology Chromatin Circadian Rhythms Complex DNA DNA Binding Diabetes Mellitus EP300 gene Environment Equilibrium Exons Foundations Generations Genetic Transcription Genome Goals Health Homeostasis Hour Human Imides In Vitro Incidence Knowledge Lead Malignant Neoplasms Mammals Mediating Metabolic syndrome Molecular Molecular Mimicry NMR Spectroscopy Outcomes Research Pathway interactions Peptidylprolyl Isomerase Physiology Premature aging syndrome Preventive Protein Dynamics Proteins Recruitment Activity Regulation Research Resolution Role Solutions Structure Techniques Testing Therapeutic Time Transactivation Transcription Coactivator Transcription Repressor/Corepressor Transcriptional Activation Domain Transcriptional Regulation Translational Research Work base cancer cell circadian pacemaker cis trans isomerization conformer fitness flexibility histone methyltransferase human disease in vivo innovation insight novel therapeutics programs public health relevance transcription factor

项目摘要

DESCRIPTION (provided by applicant): Mammals have an internal molecular clock that coordinates physiology into rhythms that coincide with the external solar day, providing enhanced evolutionary fitness by timing the peak activity of integrated biochemical processes. Loss of this internal 24-hour circadian clock leads to diabetes, metabolic syndrome, cancer, and premature aging by disrupting the temporal coordination of physiology with our behavior and the external environment. The long-term goal is to develop a deeper mechanistic understanding of how the molecular clock generates 24-hour timing in humans, in order to capitalize on this temporal regulation to develop new and innovative strategies to treat a broad spectrum of human diseases. The objective in this proposal is to identify the structural basis for transcriptional regulation by the primary circadian transcription factor, CLOCK:BMAL1, which controls expression of nearly 15% of the genome on a daily basis to drive circadian rhythms of physiology. Despite its critical importance in human physiology, very little is known about what governs the temporal switch from active to repressive CLOCK:BMAL1 complexes that create the intrinsic 24-hour period of the molecular clock. The central hypothesis is that CLOCK and BMAL1 transcriptional activation domains use intrinsic flexibility to regulate binding of activator and repressors to contribute to 24-hour timing of the molecular clock. Using nuclear magnetic resonance spectroscopy, quantitative biochemistry and cell-based studies, we will pursue two specific aims investigating 1) how a dynamic conformational switch in the BMAL1 activation domain regulates CLOCK:BMAL1 activity and 2) how competition for binding to the CLOCK activation domain regulates CLOCK:BMAL1 in normal clock function and in human cancer. Our innovative approach integrates diverse techniques from cell biology to solution NMR spectroscopy to generate biomedically relevant, atomic-level insight into clock function. The proposed research is significant, because it is expected to provide fundamentally new conceptual advances that address how CLOCK:BMAL1 works to generate 24-hour molecular rhythms and control global homeostasis. Ultimately, such knowledge has the potential to inform new strategies for basic and translational research into circadian control of human physiology.

描述（由申请人提供）：哺乳动物具有内部分子时钟，该时钟将生理学协调成与外部太阳日相吻合的节奏，从而通过定时综合生物化学过程的峰值活性来提供增强的进化适应性。这种内部24小时昼夜节律的损失导致糖尿病，代谢综合征，癌症和过早衰老，通过破坏生理学的时间协调，以我们的行为和外部环境。长期的目标是对分子时钟如何在人类中产生24小时的时间来建立更深入的机械理解，以利用这种时间调节，以制定新的创新策略来治疗广泛的人类疾病。该提案的目的是通过主要的昼夜节律转录因子时钟：BMAL1确定转录调控的结构基础，该因子每天控制近15％的基因组表达，以驱动生理的昼夜节律。尽管它在人类生理学中至关重要，但对从主动时钟转变为抑制时钟的转换的原因很少：BMAL1复合物创造了分子时钟的24小时固有的24小时。中心假设是时钟和BMAL1转录激活结构域使用固有的灵活性来调节激活因子和阻遏物的结合，从而有助于分子时钟的24小时计时。使用核磁共振光谱，定量生物化学和基于细胞的研究，我们将追求两个特定的目的研究1）BMAL1激活域中的动态构象转换如何调节时钟：BMAL1活性和2）如何竞争与时钟激活域调节时钟调节时钟：BMAL1在正常时钟和人类癌症中的竞争。我们的创新方法整合了从细胞生物学到溶液NMR光谱的多种技术，以生成对时钟功能的生物医学相关的，原子水平的见解。拟议的研究很重要，因为预计它将提供从根本上提供新的概念进步，以解决时钟：BMAL1的工作方式，以产生24小时的分子节奏并控制全球稳态。最终，这种知识有可能为昼夜节律控制人类生理学控制的新策略提供新的策略。