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Analysis of clock proteins in their non-circadian roles

分析时钟蛋白的非昼夜节律作用

基本信息

批准号：
7900653
负责人：
Jadwiga M Giebultowicz
金额：
$ 7.86万
依托单位：
OREGON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-15 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7900653
关键词：
Advanced Sleep Phase Syndrome Alleles Animal Model Animals Behavior Behavioral Binding Biochemical Biochemical Genetics Biochemistry Biological Models Biomedical Research Brain Cell Nucleus Cells Chronobiology Circadian Rhythms Clock protein Collection Complex Courtship Cytoplasm Data Defect Development Diet Disease Drosophila genus Drosophila melanogaster Drug Sensitization Event Feedback Female Fertility Fiber Food Foundations Freezing Gene Expression Gene Proteins Genes Genetic Goals Guidelines Hand Head Health Homeostasis Homologous Gene Human Immunoprecipitation Insecta Knowledge Laboratories Lead Learning Life Life Cycle Stages Light Link Malignant Neoplasms Mammals Maps Mass Spectrum Analysis Measures Messenger RNA Metabolic Metabolic Pathway Methods Missense Mutation Modeling Molecular Mutation Neuraxis Nuclear Nutrient Nutritional Nutritional status Oocytes Oogenesis Organ Ovarian Ovarian Follicle Ovary Participant Pathology Pathway interactions Pattern Peripheral Phase Phenotype Physiological Physiological Processes Physiology Play Principal Investigator Process Production Protein Analysis Protein-Restricted Diet Proteins Proteomics Reagent Recovery Regulation Reporting Reproduction Research Research Personnel Role Sampling Scientist Signal Pathway Signal Transduction Site Sleep Sleep Disorders Stretching Structure Surface System Testing Time Tissues United States National Institutes of Health Vertebrates Work base circadian pacemaker comparative egg fly gene function human disease immunocytochemistry indexing insight interest mutant novel null mutation nutrition protein complex research study response tool trait

项目摘要

Circadian clocks are evolutionary conserved coordinators of behavioral and physiological processes. Malfunctions of circadian clocks in humans lead to serious pathologies such as sleep disorders and cancer. Circadian timekeeping is accomplished by molecular feedback loops that involve several clock genes and their proteins. The role of two genes period(per)and timeless(tim) has been well established in the clock feedback loop, which operates in the model organism Drosophila melanogaster. The products of these two genes, proteins PER and TIM,translocate to cell nuclei and are subsequently degraded; both events are essential for clock function. Surprisingly, in the ovary, these proteins behave differently. Their levels do not cycle; instead, they remain stable and cytoplasmic at all times. We have evidence that non-circadian expression of PER and TIM in the ovary may have important functions in the modulation of egg production. We hypothesize that clock genes may be interacting with components of signaling pathways that govern metabolic homeostasis and nutrient allocation. We propose to use biochemical and genetic tools to test this hypothesis in two specific aims. First, we will study genetic and biochemical interactions of PER and TIM in the ovary and test their functional significance using fecundity related phenotypes. Second, we will perform protein interaction screens to identify novel proteins that may interact with cytoplasmic PER and TIM. Results obtained in this study will give us important insights into the functional significance of non-circadian expression of clock proteins. There is increasing evidence that genes that were thought to act exclusively as clock components have other important pleiotropic roles. They act in a non-circadian manner in both fly and mammals. Therefore, understanding the non-circadian functions of clock genes in a model organism should provide valuable insights into similar processes related to human health.

生物钟是行为和生理的进化保守协调者流程.人体生物钟的故障会导致严重的疾病，如睡眠疾病和癌症。昼夜节律计时是通过分子反馈回路来实现的，涉及几个时钟基因及其蛋白质。两个基因的作用时期（每）和永恒（蒂姆）在生物模型中运作的时钟反馈回路中，果蝇这两个基因的产物，蛋白质PER和TIM，易位到细胞核并随后降解;这两个事件对于时钟功能都是必不可少的。令人惊讶的是，在卵巢中，这些蛋白质的行为不同。它们的水平不会循环;相反，它们始终保持稳定和细胞质。我们有证据表明，非昼夜表达的卵巢中的PER和TIM可能在调节卵子生产中起重要作用。我们假设时钟基因可能与信号通路的组分相互作用，控制着代谢平衡和营养分配。我们建议使用生物化学和遗传学工具来测试这一假设在两个特定的目标。首先，我们将研究遗传和生物化学卵巢中PER和TIM的相互作用，并使用生殖力测试其功能意义相关表型其次，我们将进行蛋白质相互作用筛选，以确定新的蛋白质可能与细胞质PER和TIM相互作用。这项研究的结果将使我们重要的见解的非昼夜表达的时钟蛋白的功能意义。有越来越多的证据表明，基因被认为是专门作为时钟组件具有其他重要的多效性作用。它们以非昼夜节律的方式在苍蝇和哺乳动物中起作用。因此，了解生物钟基因在模式生物中的非昼夜节律功能，为与人类健康相关的类似过程提供有价值的见解。