Genetic Mechanisms of Circadian Clock-Mediated Dietary Restriction in Drosophila

果蝇生物钟介导的饮食限制的遗传机制

基本信息

批准号：
10579030
负责人：
Dae-Sung Hwangbo
金额：
$ 44.54万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10579030
关键词：
Aging Behavior Behavioral Biological Assay Circadian Dysregulation Circadian desynchrony Complex Cues Darkness Data Diet Disease Drosophila genus Drosophila melanogaster Environment Environmental Risk Factor Enzymes Fat Body Fertility Functional disorder Gene Silencing Genes Genetic Genetic Screening Genomics Goals Health Health Promotion Homeostasis Homologous Gene Individual Intake Intervention Jet Lag Syndrome Light Link Liver Longevity Maintenance Malnutrition Mammals Mediating Metabolic Metabolism Modeling Molecular Mus Organism Outcome Output Pathway interactions Peripheral Physiological Physiology Play Public Health RNA Interference Recycling Research Resistance Role Sleep Starvation Stress System Testing Time Tissues Universities Yeasts abdominal fat circadian circadian pacemaker design dietary restriction environmental change feeding fitness fly genetic analysis genetic testing genome-wide healthspan in vivo insight knock-down literature survey metabolomics model organism molecular clock multicatalytic endopeptidase complex mutant nonhuman primate proteostasis reduced food intake response screening shift work social tool trait transcription factor transcriptome transcriptome sequencing transcriptomics undergraduate student

项目摘要

Project Summary/Abstract Dietary Restriction (DR), where caloric or diet intake is reduced but not to the point of malnutrition, extends lifespan and healthspan in model organisms from single cellular yeast to non-human primates. However, the molecular mechanisms by which DR delays aging and promotes health are not fully understood. Due to their short lifespan, versatile genetic tools, and high conservation of molecular pathways for metabolism, behavior, and aging, the fruit fly, Drosophila melanogaster, has been widely used as a model organism for DR-related research. Using Drosophila, our long-term goal is to understand how the circadian clock (genetic pathway) interacts with diets and light:dark cycles (environmental factors) to optimize organismal metabolism, physiology, and behavior that ultimately promotes health and longevity. PI’s preliminary data obtained through systemic lifespan/behavior assays and tissue- and diet-dependent transcriptomic analysis suggests a critical role of the circadian clock in the peripheral fat body (functionally homologues to the liver) for the beneficial effects of DR. The overall objective of this proposal is to understand genetic mechanisms by which circadian clocks in fat body mediate DR-dependent lifespan extension and physiological changes. For this objective, we propose to leverage versatile Drosophila genetics to test our central hypothesis, formulated based on the preliminary data and literature survey, that clock-controlled genes (CCGs) in fat body promote health and longevity by coordinating time-dependent metabolic, physiological, and behavioral homeostasis. To test this hypothesis, we propose to perform three independent yet interconnected specific aims: First, by completing a large-scale tissue specific in vivo functional screening, we will determine key CCGs and molecular pathways in fat body that are important for DR response (Aim 1). Second, by employing a genomic and metabolomic profiling, we will identify molecular and metabolic signatures responsible for DR-mediated lifespan extension through clock-controlled proteasome in fat body. Third, by applying a forced circadian misalignment (similar to jet-lag), we will determine the impact of desynchrony between the external environmental time and the internal molecular clock on DR and CCGs (Aim 3). This study is meritorious because it will generate outcomes that provide insight into how the circadian clock orchestrates environmental cues to promote health and longevity. This study also strengthens the research environment of undergraduate students at the University of Louisville because it is designed to be completed by a research team primarily composed of undergraduate students at the University.

项目概要/摘要饮食限制（DR），即减少热量或饮食摄入，但未达到营养不良的程度，延长了从单细胞酵母到非人类灵长类动物的模型生物的寿命和健康期。 DR 延缓衰老和促进健康的分子机制尚不完全清楚。寿命短、通用的遗传工具以及新陈代谢、行为、果蝇（Drosophila melanogaster）已被广泛用作 DR 相关的模式生物利用果蝇的研究，我们的长期目标是了解生物钟（遗传途径）是如何运作的。与饮食和光相互作用：暗循环（环境因素）以优化生物代谢、生理学、 PI通过系统获得的初步数据最终促进健康和长寿的行为。寿命/行为测定以及组织和饮食依赖性转录组分析表明，外周脂肪体（功能上与肝脏同源）的生物钟对于 DR 的有益作用。该提案的总体目标是了解脂肪生物钟的遗传机制身体介导 DR 依赖性寿命延长和生理变化。为此，我们建议：利用多功能果蝇遗传学来测试我们根据初步数据制定的中心假设和文献调查表明，脂肪体内的时钟控制基因（CCG）通过以下方式促进健康和长寿：协调时间依赖性代谢、生理和行为稳态为了检验这一假设。提议实现三个独立但相互关联的具体目标：首先，通过完成大规模组织特定的体内功能筛选，我们将确定脂肪体内的关键CCG和分子通路对于 DR 反应很重要（目标 1）其次，通过采用基因组和代谢组学分析，我们将确定。分子和代谢特征通过时钟控制负责 DR 介导的寿命延长第三，通过施加强制昼夜节律失调（类似于时差），我们将确定。外部环境时间与内部分子钟不同步对 DR 和 CCG（目标 3）。这项研究是有价值的，因为它将产生深入了解如何进行的结果。这项研究还强化了生物钟协调环境线索以促进健康和长寿。路易斯维尔大学本科生的研究环境，因为它旨在由主要由大学本科生组成的研究团队完成。