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

研究母体代谢重编程在后代生理和衰老中的作用

基本信息

批准号：
10665591
负责人：
Matthew Sieber
金额：
$ 43.22万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10665591
关键词：
Adult Aging Animals Biochemical Biological Models Cell Lineage Cell model Cells Cellular Metabolic Process ChIP-seq Child Chromatin Complex DNA Data Defect Development Diabetic mother Disease Disease susceptibility Drosophila genus Embryo Environment Environmental Risk Factor Epigenetic Process Equilibrium Exhibits Female Foundations Functional disorder Genes Genetic Genetic Transcription Glucose Glutathione Glycogen Goals Health Heritability Histone Acetylation Homeostasis Human Incidence Individual Inherited Insulin Intestines Life Lipids Longevity Mammalian Cell Mediating Metabolic Metabolic Diseases Metabolic dysfunction Metabolic syndrome Metabolism Methods Mitochondria Modeling Molecular Mothers Mus Nuclear Nutrient Oocytes Oogenesis Oxidation-Reduction Partner in relationship Persons Phenotype Physiology Play Predisposition Prevalence Process Promoter Regions Research Risk Role Signal Transduction Small RNA Speed System Testing Tissues Triglyceride Metabolism Triglycerides Work aged blood glucose regulation cancer initiation carbohydrate metabolism diabetic disability experimental study healthspan histone methylation in vivo insight insulin signaling male metabolic abnormality assessment metabolomics novel nutrition offspring oxidation premature programs respiratory sperm cell stem cells tool transcription factor transmission process tumor progression

项目摘要

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.

抽象的代谢功能障碍是影响所有系统寿命的主要因素之一。线粒体缺陷为已知在衰老期间会导致组织功能障碍。碳水化合物代谢，脂质氧化的改变，氧化还原代谢都被证明在许多过程中都起着重要作用，可以帮助决定寿命。可以决定人类寿命和衰老的一个主要因素是代谢综合征的开始。超过在过去的30年中，代谢疾病的患病率急剧上升，目前为1/3 全球人患有代谢综合征。而遗传学，环境和营养很重要许多最近的研究表明，孕产妇的破坏代谢可以对后代生理和衰老产生深远的影响。尽管许多研究都检查了染色质状态和小RNA可以解释母体代谢对后代疾病的遗传力实际上，这些研究支持了其他因素有助于代谢综合征的遗传力的观念。与精子不同，只有对早期胚胎有助于DNA，卵母细胞提供了复杂的库存代谢物，储存的营养和线粒体。我们的研究利用了果蝇卵子发生系统作为隔离大量分阶段卵母细胞和胚胎的工具，以进行深入的生化和对调节卵母细胞生理和代谢的机制的代谢组学研究。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化卵母细胞中影响后代代谢的机制。在此提案中，我们将研究如何变化老年母亲的系统性代谢会影响后代生理和代谢的重编程。在此外，我们还将检查重编程后的后代是否显示出发生的代谢转移的变化通常在衰老期间。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信号重编程后代生理学。我们还将定义染色质景观的变化我们在重编程后代观察到的转录移位。我们的长期目标是利用这些研究提供一个机械平台，以研究其他系统（例如小鼠和）的代谢重编程哺乳动物细胞模型及其如何影响后代生理和衰老。总体而言，这一提议挑战我们所有人对疾病的遗传力的教条思想，并探讨了新颖的概念卵母细胞代谢的变化可以在衰老过程中重新编程后代生理和代谢。