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 在衰老过程中导致组织功能障碍。碳水化合物代谢，脂质氧化， 和氧化还原代谢都被证明在许多过程中发挥重要作用， 寿命代谢综合征的发病是决定人类寿命和衰老的一个主要因素。超过 在过去的30年里，代谢性疾病的患病率急剧上升，目前1/3的 全世界的人都患有代谢综合征。虽然遗传、环境和营养在 在代谢功能障碍和寿命中的作用，最近的许多研究表明， 代谢可对后代生理学和衰老产生深远影响。虽然许多研究已经检查了 染色质状态和小RNA来解释母体代谢对后代疾病的遗传性 事实上，这些研究支持了其他因素对代谢综合征的遗传性有影响的观点。 与精子不同，精子只为早期胚胎提供DNA，卵母细胞提供了一个复杂的储存， 代谢物、储存的营养物质和线粒体传递给后代。我们的研究利用了果蝇卵子发生 系统作为分离大量分期卵母细胞和胚胎的工具，以进行深入的生化和 代谢组学研究调节卵母细胞生理和代谢的机制。这些工具 结合果蝇遗传学的速度和力量，使我们能够识别和表征生物化学， 卵母细胞中影响后代代谢的机制。在本建议书中，我们将研究 老年母亲的全身代谢影响后代生理和代谢的重新编程。在 此外，我们还将检查重编程的后代是否表现出代谢变化的改变， 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一个 重新编程后代生理的信号。我们还将定义染色质景观的变化， 我们在重编程后代中观察到的转录转变。我们的长期目标是利用这些研究， 提供了一个机制平台来研究其他系统中的代谢重编程，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。总的来说，这一提议挑战了 我们都对疾病的遗传性有教条的想法，并探讨了新的概念， 卵母细胞代谢的变化可以在老化过程中重新编程后代的生理和代谢。

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.