Metabolic Landscape of the Aging Lung

衰老肺的代谢景观

基本信息

批准号：
10613474
负责人：
Jarrod W. Barnes
金额：
$ 78.53万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
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：
2020-05-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10613474
关键词：
3-Dimensional 5&apos -AMP-activated protein kinase Acceleration Acute Acute Disease Age Years Aging Animal Model Bioenergetics Biology of Aging Bleomycin Cell Aging Cell Cycle Cell physiology Cells Chronic Chronic Disease Chronic Obstructive Pulmonary Disease Data Disease Elderly Enzymes Epigenetic Process Epithelial Cells Fibroblasts Fibrosis Formulation Gerontology Glucose Human Hydrolase Impairment In Vitro Inflammation Injury Link Longevity Lung Lung diseases Metabolic Metabolic Pathway Metabolic stress Metabolism Mitochondria Modeling Modification Molecular Mus Myofibroblast Nutrient O-GlcNAc transferase Organoids Oxidation-Reduction Pathway interactions Patients Pharmacotherapy Phenotype Plasma Post-Translational Protein Processing Predisposition Process Program Research Project Grants Proliferating Pulmonary Emphysema Pulmonary Fibrosis Reaction Regulation Reporting Research Resolution Risk Factors Role Sampling Signal Transduction Smooth Muscle Stress Structure of parenchyma of lung Testing Tissues aerobic glycolysis age related aged alveolar epithelium cell type cohort detection of nutrient exhaustion glycosylation healthspan human subject idiopathic pulmonary fibrosis in vivo loss of function lung injury metabolomics middle age mitochondrial dysfunction normal aging nutrient metabolism personalized approach predict responsiveness primary pulmonary hypertension prospective proteostasis response senescence sensor stem cells stressor telomere young adult

项目摘要

PROJECT SUMMARY Aging is a major risk factor for acute and chronic diseases of the lung, including emphysema and idiopathic pulmonary fibrosis. The biology of aging has rapidly advanced in recent years, and several hallmarks of aging including, dysregulated nutrient sensing, mitochondrial dysfunction, and cellular senescence have been proposed. However, the precise metabolic underpinnings of how these hallmarks regulate lifespan/healthspan and accelerated aging have not yet been determined. Recent studies indicate that aging is associated with loss of cellular plasticity and sustained fibroblast senescence that leads to persistent/non-resolving fibrosis in response to lung injury. Interestingly, glycosylation reactions such as the O-linked N-Acetylglucosamine (O-GlcNAc) modification have been integrally linked to metabolic/nutrient- and stress-responsive signaling, including the regulation of AMPK. We previously reported that the O-GlcNAc transferase (OGT), through altered glucose utilization and metabolism, regulates smooth muscle proliferation associated with accelerated progression of idiopathic pulmonary arterial hypertension (IPAH). OGT is a metabolic stress `sensor' and is responsible for the O-GlcNAc modification of proteins involved in cell signaling, cell cycle, proliferation/senescence, mitochondrial bioenergetics, and nutrient metabolism. In addition, OGA (O-GlcNAc hydrolase), the O-GlcNAc removing enzyme, is involved in these cellular processes. O-GlcNAc/OGT/OGA (hereby, termed the O-GlcNAc axis), thus, may regulate multiple aging-related hallmarks. The impact of the O-GlcNAc axis as a metabolic sensor and regulator of cellular senescence and aging in IPF, as well as other diseases of the aging lung, has not been studied. Our hypothesis to be tested in this proposal is that altered metabolic sensing by the O-GlcNAc signaling axis predisposes to cellular senescence and accelerated aging in IPF. We will test this hypothesis using the following specific aims: (1) Investigate the molecular mechanism(s) of the O-GlcNAc axis on accelerated aging and cellular senescence in IPF; (2) Determine whether the O-GlcNAc axis regulates cellular senescence and capacity for fibrosis resolution in aged mice.; and (3) Determine the metabolomic and glycomic profiles in normal human lung aging and in IPF. Completion of these aims will: (a) identify the O-GlcNAc axis as a key hub in metabolic dysregulation associated with aging; (b) demonstrate the O-GlcNAc axis on specific cell types in the lung and their susceptibility and contribution to disease and accelerated aging; and (c) demonstrate that one or more metabolic pathways are regulated by the O-GlcNAc axis in the age-related lung disease, IPF.

项目概要衰老是急性和慢性肺部疾病的主要危险因素，包括肺气肿和特发性肺纤维化。近年来，衰老的生物学进展迅速，有几个特点衰老的因素包括营养感应失调、线粒体功能障碍和细胞衰老被提议。然而，这些标志如何调节的精确代谢基础寿命/健康寿命和加速衰老尚未确定。最近的研究表明，衰老与细胞可塑性和持续成纤维细胞的丧失有关衰老导致肺损伤引起的持续性/非消退性纤维化。有趣的是，糖基化 O-连接的 N-乙酰葡糖胺 (O-GlcNAc) 修饰等反应已与代谢/营养和压力响应信号，包括 AMPK 的调节。我们之前报道过 O-GlcNAc 转移酶 (OGT) 通过改变葡萄糖利用和代谢，调节平滑肌与特发性肺动脉高压加速进展相关的肌肉增殖（异丙醇）。 OGT 是一种代谢应激“传感器”，负责相关蛋白质的 O-GlcNAc 修饰细胞信号传导、细胞周期、增殖/衰老、线粒体生物能学和营养代谢。在此外，O-GlcNAc 去除酶 OGA（O-GlcNAc 水解酶）也参与这些细胞过程。因此，O-GlcNAc/OGT/OGA（特此称为 O-GlcNAc 轴）可以调节多种与衰老相关的特征。 O-GlcNAc 轴作为 IPF 中细胞衰老和老化的代谢传感器和调节器的影响，以及其他肺部老化疾病，尚未得到研究。我们在本提案中要测试的假设是 O-GlcNAc 信号传导改变了代谢传感 IPF 中轴易导致细胞衰老和加速衰老。我们将使用以下方法检验这个假设具体目标如下：（1）研究O-GlcNAc轴加速衰老的分子机制和 IPF 中的细胞衰老； (2)确定O-GlcNAc轴是否调节细胞衰老和老年小鼠纤维化消退的能力。 (3) 确定正常人的代谢组学和糖组学特征人类肺部衰老和特发性肺纤维化（IPF）。完成这些目标将：(a) 将 O-GlcNAc 轴确定为关键枢纽与衰老相关的代谢失调； (b) 展示特定细胞类型上的 O-GlcNAc 轴肺及其对疾病和加速衰老的易感性和贡献； (c) 证明一个或在年龄相关性肺病（IPF）中，更多的代谢途径受到 O-GlcNAc 轴的调节。