Interrogation of the cellular and subcellular architecture of nutrient metabolism in conditions of dietary restriction

饮食限制条件下营养代谢的细胞和亚细胞结构的询问

• 批准号: 10910343
• 负责人: Rafael Arrojo e Drigo
• 金额: $ 39.63万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10910343
• 关键词: Age of Onset; Aging; Animals; Architecture; Autophagocytosis; Caenorhabditis elegans; Cell Aging; Cell physiology; Cells; Cellular biology; Chronic; Communication; Complement; Data; Defect; Deterioration; Disease; Electron Microscopy; Endoplasmic Reticulum; Endosomes; Event; Fluorescence Microscopy; Functional disorder; Glucose; Goals; Hepatocyte; Homeostasis; Image; Imaging technology; In Situ; Intervention; Isotope Labeling; Isotopes; Label; Link; Lipids; Logic; Longevity; Macronutrients Nutrition; Maintenance; Maps; Mediating; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Morphology; Mus; Nutrient; Onset of illness; Organelles; Pattern; Performance; Physiologic pulse; Play; Proteins; Resolution; Resources; Role; Route; Series; Shapes; Site; Stress; Structure; Subcellular structure; age related; aged; biological adaptation to stress; birth control; deep learning; dietary restriction; endoplasmic reticulum stress; experimental study; fitness; functional decline; healthy aging; imaging approach; in vivo; insight; microscopic imaging; mouse model; novel therapeutics; nutrient metabolism; peroxisome; resilience; response; spatial relationship; stable isotope; trafficking; uptake

Project Summary/Abstract The re-allocation of metabolic resources towards cell processes that promote somatic maintenance is a long- held hypothesis to explain how diverse longevity paradigms promote healthier aging. One of the best models of this hypothesis is dietary restriction (DR), which optimizes metabolic efficiency while maintaining animal fitness and longevity. However, we possess surprisingly little insight into how specific nutrient resources are differentially utilized at the cell level during DR. In addition to altering metabolic processes, DR promotes a dramatic remodeling of organelle structures and functions. Increasingly we understand that not only is the structure of a discrete organelle critical for its functional state, but also the spatial relationships and contact sites formed between different organelle networks. The restructuring of the overall subcellular architecture thus plays a critical role in determining metabolic performance. However, our preliminary data suggest that age-dependent accumulation of molecular damage causes remodeling of the endoplasmic reticulum (ER), a hub of inter- organellar communication. Our overarching hypothesis is thus that remodeling of inter-organelle interactions is is both a key route by which aging cells lose functional resilience and an essential mechanism of DR-mediated reprogramming of metabolism. To advance this hypothesis we propose to exploit new correlative electron microscopy (EM) and stable isotope imaging technology in a combination of mouse and C. elegans models to establish a framework for how DR restructures the organelle interactome and re-allocates nutrient flux between organelles. Altogether this proposal aims to establish a framework for how DR remodels the organelle interactome to promote healthy aging with a focus on the role of the ER.

项目总结/摘要 将代谢资源重新分配给促进体细胞维持的细胞过程是一个长期的过程， 该假说解释了不同的长寿模式如何促进更健康的老龄化。最好的模型之一 这一假说是饮食限制（DR），它在保持动物健康的同时优化代谢效率 和长寿。然而，令人惊讶的是，我们对特定营养资源的差异性知之甚少。 除了改变代谢过程外，DR还促进了细胞水平的显著变化。 细胞器结构和功能的重塑。我们越来越认识到， 离散的细胞器对其功能状态至关重要，而且还形成了空间关系和接触部位 不同细胞器网络之间的联系因此，整个亚细胞结构的重组在细胞内起着关键的作用。 决定代谢性能的作用。然而，我们的初步数据表明， 分子损伤的积累导致内质网（ER）的重塑，内质网是细胞间相互作用的枢纽。 细胞器通讯因此，我们的总体假设是，细胞器间相互作用的重塑是 是衰老细胞失去功能弹性的关键途径，也是DR介导的 重新编程新陈代谢。为了推进这一假设，我们提出利用新的关联电子 显微镜（EM）和稳定同位素成像技术在小鼠和C. elegans模型， 建立DR如何重组细胞器相互作用组和重新分配营养通量之间的框架 细胞器总而言之，这个建议的目的是建立一个框架，如何DR重塑细胞器 interactome促进健康老龄化，重点是ER的作用。