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：
7169215
负责人：
Jadwiga M Giebultowicz
金额：
$ 26.11万
依托单位：
OREGON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-01 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7169215
关键词：
Advanced Sleep Phase Syndrome Alleles Animal Model Animals Behavior Behavioral Binding 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 Numbers Nutrient Nutritional Nutritional status Oocytes Oogenesis Organ Ovarian Ovarian Follicle Ovary Participant Pathology Pathway interactions Pattern Peripheral Personal Satisfaction Phase Phenotype Physiological Physiological Processes Physiology Play Principal Investigator Process Production Protein Analysis Protein-Restricted Diet Proteins Proteomics Rate Reagent Recovery Regulation Reporting Reproduction Research Research Personnel Role Sampling Scientist Signal Pathway Signal Transduction Site Sleep Sleep Disorders Stretching Structure Surface System Testing Thinking Time Tissues United States National Institutes of Health Vertebrates Work base circadian pacemaker comparative desire egg fly gene function human disease immunocytochemistry indexing insight interest mutant novel null mutation nutrition research study response tool trait

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：生物钟是行为和生理过程的进化保守协调器。人类生物钟故障会导致严重的疾病，例如睡眠障碍和癌症。昼夜节律计时是通过涉及多个时钟基因及其蛋白质的分子反馈回路来完成的。 period (per) 和 timeless (tim) 两个基因的作用已在生物钟反馈环路中得到很好的确立，该环路在模式生物果蝇中发挥作用。这两个基因的产物，蛋白质PER和TIM，易位到细胞核并随后被降解；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，这些蛋白质的行为有所不同。它们的水平不循环；相反，它们始终保持稳定和细胞质。我们有证据表明，卵巢中 PER 和 TIM 的非昼夜节律表达可能在调节产蛋量方面具有重要功能。我们假设时钟基因可能与控制代谢稳态和营养分配的信号通路成分相互作用。我们建议使用生化和遗传工具在两个特定目标上检验这一假设。首先，我们将研究卵巢中 PER 和 TIM 的遗传和生化相互作用，并使用生育力相关表型测试它们的功能意义。其次，我们将进行蛋白质相互作用筛选，以鉴定可能与细胞质 PER 和 TIM 相互作用的新蛋白质。这项研究获得的结果将为我们提供有关时钟蛋白非昼夜节律表达的功能意义的重要见解。越来越多的证据表明，被认为仅充当时钟成分的基因还具有其他重要的多效性作用。它们在苍蝇和哺乳动物中都以非昼夜节律的方式活动。因此，了解模式生物中时钟基因的非昼夜节律功能应该为与人类健康相关的类似过程提供有价值的见解。