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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/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提出假设来解释不同的长寿范式如何促进更健康的衰老。最好的模型之一这个假设是饮食限制（DR），它可以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如何差异化知之甚少。在 DR 期间在细胞水平上使用。除了改变代谢过程外，DR 还可以显着促进细胞器结构和功能的重塑。我们越来越明白，结构不仅是离散的细胞器对其功能状态至关重要，而且对其形成的空间关系和接触位点也至关重要不同细胞器网络之间。因此，整个亚细胞结构的重组起着至关重要的作用。决定代谢性能的作用。然而，我们的初步数据表明，年龄依赖性分子损伤的积累导致内质网（ER）的重塑，内质网是细胞间的枢纽。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既是衰老细胞失去功能弹性的关键途径，也是 DR 介导的重要机制新陈代谢的重新编程。为了推进这一假设，我们建议利用新的相关电子显微镜（EM）和稳定同位素成像技术结合小鼠和线虫模型建立一个框架，说明 DR 如何重组细胞器相互作用组并重新分配细胞之间的营养通量细胞器。总而言之，该提案旨在建立一个 DR 如何重塑细胞器的框架相互作用组促进健康衰老，重点关注 ER 的作用。