Novel Circadian Mutant of Drosophila

果蝇的新型昼夜节律突变体

基本信息

批准号：
8197729
负责人：
JEFFREY L PRICE
金额：
$ 30.28万
依托单位：
UNIVERSITY OF MISSOURI KANSAS CITY
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-04-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197729
关键词：
Address Adult Affect Alanine Antibodies Area Aspartate Behavior Behavioral Binding Biochemical Biochemical Process Biological C-terminal Cell Line Cell Nucleus Cell physiology Cells Circadian Rhythms Clinical Clock protein Complex Cytoplasm Drosophila genus Endocrine Event Feedback Financial compensation Future Goals Head Human Knowledge Link Malignant Neoplasms Mammals Mass Spectrum Analysis Mental disorders Metabolic Diseases Modern Medicine Molecular Mutate Mutation Nuclear Outcome Pharmaceutical Preparations Phosphoric Monoester Hydrolases Phosphorylation Phosphorylation Site Phosphotransferases Physiology Process Protein Kinase Protein phosphatase Proteins Proteomics Regulation Role Scientist Serine Site Sleep Sleep Wake Cycle Temperature Threonine Time Work base casein kinase I circadian pacemaker clinically relevant drug efficacy drug metabolism fly human disease in vivo interest mimetics mutant novel promoter protein complex protein protein interaction public health relevance transcription factor

项目摘要

DESCRIPTION (provided by applicant): Many behavioral, cellular and biochemical processes are controlled by an endogenous circadian clock, and the molecular mechanisms underlying these self-sustaining circadian clocks are of interest to both clinicians and basic scientists. The clinical relevance of circadian rhythms is most obvious in their control of sleep/wake cycles, but many other medically relevant processes are also regulated by circadian rhythms. Endocrine function, cancer regulation, psychiatric disorders and drug metabolism are all affected by circadian clocks, and therefore knowledge of their basic mechanism can contribute to many areas of modern medicine. At the core of this molecular mechanism in mammals and flies are oscillations of the PER protein, which are controlled at the post-translational level by the activities of several kinases, including the DBT casein kinase I. This application proposes to elucidate the mechanism by which DBT regulates the oscillations of PER. The first aim will identify other proteins which interact with DBT and PER to regulate the activity of DBT and bring about the biochemical consequences of PER's phosphorylation by DBT. This aim will employ both a Drosophila cell culture line (S2 cells) as well as adult fly heads. Aim 2 will identify the sites within PER that are phosphorylated by DBT and other kinases, under various conditions relevant to circadian function in the adult fly head. A mass-spectrometry-based proteomic approach will be a major focus of both Aims 1 and 2. Finally, Aim 3 will address how protein/protein interactions and phosphorylation at particular sites with PER regulate processes involving PER and DBT. Aim 3 will therefore address the biological consequences of the interactions and phosphorylation sites identified in Aims 1 and 2. PUBLIC HEALTH RELEVANCE: Circadian rhythms are daily cycles of behavior and physiology, as exemplified by our sleep/wake behavior, and they affect drug efficacy, cancer, metabolism and psychological disorders. This application seeks to understand one of the key biochemical mechanisms that produce the circadian clock. The mechanism is very amenable to treatment with drugs, so the understanding may affect treatments of a number of human diseases.

描述（由申请人提供）：许多行为、细胞和生化过程是由内源性生物钟控制的，这些自我维持生物钟背后的分子机制引起了临床医生和基础科学家的兴趣。昼夜节律的临床相关性在其对睡眠/觉醒周期的控制中最为明显，但许多其他医学相关过程也受昼夜节律的调节。内分泌功能、癌症调节、精神疾病和药物代谢都受到生物钟的影响，因此了解其基本机制可以为现代医学的许多领域做出贡献。哺乳动物和果蝇中这种分子机制的核心是 PER 蛋白的振荡，该振荡在翻译后水平上由几种激酶（包括 DBT 酪蛋白激酶 I）的活性控制。本申请旨在阐明 PER 蛋白的振荡机制DBT 调节 PER 的振荡。第一个目标是鉴定与 DBT 和 PER 相互作用的其他蛋白质，以调节 DBT 的活性，并引起 DBT 磷酸化 PER 的生化后果。该目标将采用果蝇细胞培养系（S2 细胞）以及成年果蝇头。目标 2 将确定在与成年果蝇头部昼夜节律功能相关的各种条件下 PER 内被 DBT 和其他激酶磷酸化的位点。基于质谱的蛋白质组学方法将是目标 1 和 2 的主要焦点。最后，目标 3 将解决蛋白质/蛋白质相互作用以及特定位点的磷酸化如何通过 PER 调节涉及 PER 和 DBT 的过程。因此，目标 3 将解决目标 1 和 2 中确定的相互作用和磷酸化位点的生物学后果。公共卫生相关性：昼夜节律是行为和生理的日常周期，如我们的睡眠/觉醒行为所示，它们影响药物疗效、癌症、新陈代谢和心理障碍。该应用旨在了解产生生物钟的关键生化机制之一。该机制非常适合药物治疗，因此对该机制的了解可能会影响许多人类疾病的治疗。