Genetic Mechanisms of Circadian Clock-Mediated Dietary Restriction in Drosophila

项目摘要/摘要 饮食限制(DR)，即减少卡路里或饮食摄入量，但不到营养不良的程度，延长了 从单细胞酵母到非人类灵长类动物的模式生物的寿命和健康寿命。然而， DR延缓衰老和促进健康的分子机制尚不完全清楚。由于他们的 寿命短，基因工具多样，新陈代谢，行为， 随着年龄的增长，果蝇，果蝇，黑腹果蝇，已经被广泛用作DR相关的模式生物 研究。利用果蝇，我们的长期目标是了解生物钟(遗传途径)是如何 与饮食和光相互作用：黑暗循环(环境因素)，以优化生物新陈代谢，生理学， 以及最终促进健康和长寿的行为。PI通过系统获得的初步数据 寿命/行为分析以及组织和饮食依赖的转录分析表明， 外周脂肪体的生物钟(在功能上与肝脏同源)对DR的有益影响。 这项提案的总体目标是了解脂肪昼夜节律的遗传机制。 机体介导依赖DR的寿命延长和生理变化。为达致这个目标，我们建议 利用多才多艺的果蝇遗传学来测试我们的中心假设，该假设是基于初步数据提出的 和文献调查，脂肪体内的时钟控制基因(CCGs)通过以下方式促进健康和长寿 协调依赖时间的代谢、生理和行为动态平衡。为了检验这一假设，我们 建议执行三个独立但又相互关联的具体目标：第一，通过完成一个大规模的组织 特定的体内功能筛选，我们将确定关键的CCG和脂肪体中的分子通路 对灾难恢复响应很重要(目标1)。其次，通过使用基因组和新陈代谢图谱，我们将识别 通过时钟控制DR介导寿命延长的分子和代谢特征 脂肪体中的蛋白酶体。第三，通过应用强制昼夜节律失调(类似于时差)，我们将确定 外部环境时间和内部分子时钟之间的不同步对DR和 CCGs(目标3)。这项研究是有价值的，因为它将产生一些结果，为深入了解 生物钟协调环境线索，以促进健康和长寿。这项研究也加强了 路易斯维尔大学本科生的研究环境，因为它旨在 由一个主要由大学本科生组成的研究小组完成。

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.