Genetic Mechanisms of Circadian Clock-Mediated Dietary Restriction in Drosophila

项目概要/摘要 饮食限制（DR），即减少热量或饮食摄入，但不至于营养不良， 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。但 DR延缓衰老和促进健康的分子机制尚未完全了解。由于其 短寿命，多功能的遗传工具，以及代谢，行为， 果蝇（Drosophila melanogaster）已被广泛用作DR相关的模式生物。 research.利用果蝇，我们的长期目标是了解生物钟（遗传途径） 与饮食和光相互作用：黑暗周期（环境因素），以优化生物体代谢，生理学， 以及最终促进健康和长寿的行为。主要研究者的初步数据通过系统性 寿命/行为测定和组织和饮食依赖性转录组学分析表明， 外周脂肪体（与肝脏功能同源）的昼夜节律钟，以获得DR的有益效果。 这项建议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 利用多功能的果蝇遗传学来检验我们的中心假设，根据初步数据制定 和文献调查，脂肪体中的时钟控制基因（CCGs）通过以下方式促进健康和长寿 协调时间依赖性代谢、生理和行为的稳态。为了验证这个假设，我们 我建议执行三个独立但相互关联的具体目标：第一，通过完成一个大规模的组织 具体的体内功能筛选，我们将确定关键的CCG和脂肪体的分子途径， 对于DR响应很重要（目标1）。其次，通过采用基因组学和代谢组学分析，我们将确定 分子和代谢特征负责DR介导的寿命延长，通过时钟控制 脂肪体蛋白酶体。第三，通过应用强迫昼夜节律失调（类似于时差），我们将确定 外部环境时间与体内分子钟的离散度对DR的影响， CCG（目标3）。这项研究是有价值的，因为它将产生的结果可以深入了解 生物钟协调环境线索以促进健康和长寿。这项研究还加强了 路易斯维尔大学本科生的研究环境，因为它的目的是 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.