Investigating the role of maternal metabolic reprogramming in progeny physiology and aging

摘要 代谢功能障碍是影响所有系统寿命的主要因素之一。线粒体缺陷是 已知会在衰老过程中导致组织功能障碍。碳水化合物代谢的改变，脂肪氧化， 和氧化还原代谢都被证明在许多有助于口述的过程中发挥着重要作用 寿命。决定人类寿命和衰老的一个主要因素是代谢综合征的发病。完毕 在过去的30年里，代谢性疾病的患病率急剧上升，目前有三分之一的人 全世界的人都患有代谢综合征。虽然遗传、环境和营养因素起着重要作用 在代谢功能障碍和寿命中的作用，许多最近的研究表明，母亲的代谢紊乱 新陈代谢可以对后代的生理和衰老产生深远的影响。虽然许多研究都检查了 染色质状态和小RNA解释母体代谢对子代疾病的遗传性 事实上，这些研究支持这样一种观点，即其他因素有助于代谢综合征的遗传性。 与精子不同，精子只为早期胚胎提供DNA，卵母细胞提供了复杂的 代谢物、储存的营养物质和线粒体传给后代。我们的研究探索了果蝇的卵子发生 系统作为分离大量分期卵母细胞和胚胎的工具，进行深入的生化和 代谢组学研究卵母细胞生理和新陈代谢的调节机制。这些工具 结合果蝇的速度和力量，遗传学使我们能够识别和表征生化 卵母细胞中影响子代代谢的机制。在本提案中，我们将研究如何改变 老年母亲的系统代谢影响子代生理和代谢的重新编程。在……里面 此外，我们将检查重新编程的后代是否表现出对发生的代谢变化的改变 通常在老化过程中。我们将测试胰岛素介导的卵母细胞氧化还原代谢的变化是否提供了 对后代生理进行重新编程的信号。我们还将定义作为基础的染色质景观的变化 我们在重新编程的后代中观察到的转录变化。我们的长期目标是利用这些研究 提供一个机械平台来研究其他系统中的代谢重新编程，如小鼠和 哺乳动物细胞模型，以及它如何影响后代生理和衰老。总体而言，这项提案面临挑战 我们都有关于疾病遗传性的教条思想，并探索了 在衰老过程中，卵母细胞代谢的变化可以重新编程后代的生理和新陈代谢。

Abstract Metabolic dysfunction is one of the major factors that impact lifespan in all systems. Mitochondrial defects are known to contribute to tissue dysfunction during aging. Alterations in carbohydrate metabolism, lipid oxidation, and redox metabolism have all been shown to play significant roles in many processes that can help dictate lifespan. One major factor that can dictate human lifespan and aging is the onset of metabolic syndrome. Over the past 30 years there has been a dramatic rise in the prevalence of metabolic disease and currently 1/3 of people world-wide suffer from metabolic syndrome. While genetics, environment, and nutrition play important roles in metabolic disfunction and lifespan, many recent studies have shown that disruptions in maternal metabolism can have a profound impact on progeny physiology and aging. While many studies have examined chromatin state and small RNAs to explain the heritability that maternal metabolism has on progeny disease these studies, in fact, support the idea that other factors contribute to the heritability of metabolic syndrome. Unlike sperm, that only contribute DNA to the early embryo, the oocyte provides a complex stockpile of metabolites, stored nutrients, and mitochondria to the progeny. Our research exploits the Drosophila oogenesis system as a tool to isolate large amounts of staged oocytes and embryos to conduct in-depth biochemical and metabolomics studies of the mechanisms that regulate oocyte physiology and metabolism. These tools combined with the speed and power of Drosophila genetics allow us to identify and characterize biochemical mechanisms in the oocyte that impact progeny metabolism. In this proposal we will examine how changes in systemic metabolism in aged mothers impact the reprogramming of progeny physiology and metabolism. In addition, we will examine whether reprogrammed progeny exhibit alterations to the metabolic shifts that occur normally during aging. We will test whether insulin-mediated changes in oocyte redox metabolism provides a signal that reprograms progeny physiology. We will also define the changes in chromatin landscape that underlie the transcriptional shift we observed in reprogrammed progeny. Our long-term goal is to use these studies to provide a mechanistic platform to study metabolic reprogramming in other systems, such as mice and mammalian cell models, and how it impacts progeny physiology and aging. Overall, this proposal challenges the dogmatic ideas we all have about the heritability of disease and explores the novel concept that changes in oocyte metabolism can reprogram progeny physiology and metabolism during aging.