Metabolic Landscape of the Aging Lung

衰老肺的代谢景观

• 批准号: 10165817
• 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
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10165817
• 关键词: 3-Dimensional; 5' -AMP-activated protein kinase; Acute; Acute Disease; Age-Years; Aging; Animal Model; Bioenergetics; Biology of Aging; Bleomycin; Cell Aging; Cell Cycle; Cell physiology; Cells; Chronic; Chronic Obstructive Airway Disease; Chronic lung 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; Protein Kinase; 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; base; 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

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.

项目总结 老龄化是肺部急慢性疾病的主要风险因素，包括肺气肿和 特发性肺纤维化。近年来，衰老的生物学研究进展迅速，有几个特点 衰老包括营养感知失调、线粒体功能障碍和细胞衰老 已被提出。然而，这些特征如何调节的确切代谢基础 寿命/健康寿命和加速衰老尚未确定。 最近的研究表明，衰老与细胞可塑性的丧失和成纤维细胞的持续存在有关 对肺损伤的反应导致持续性/未消退的纤维化的衰老。有趣的是，糖基化 O-连接N-乙酰氨基葡萄糖(O-GlcNAc)修饰等反应与 代谢/营养和胁迫反应信号，包括AMPK的调节。我们之前曾报道过 O-GlcNAc转移酶(OGT)通过改变葡萄糖的利用和代谢来调节平滑 肌肉增殖与特发性肺动脉高压进展加速相关 (IPAH)。OGT是一种新陈代谢应激“传感器”，负责相关蛋白质的O-GlcNAc修饰 在细胞信号、细胞周期、增殖/衰老、线粒体生物能量学和营养代谢方面。在……里面 此外，O-GlcNAc去除酶OGA(O-GlcNAc水解酶)也参与了这些细胞过程。 因此，O-GlcNAc/OGT/OGA(这里称为O-GlcNAc轴)可能调节多种与衰老相关的标志。 O-GlcNAc轴作为代谢感受器和细胞衰老调节器在IPF中的影响， 以及其他衰老的肺部疾病，还没有被研究过。 我们的假设将在这一提议中得到验证，即O-GlcNAc信号改变了新陈代谢感觉 在IPF中，AXIS易导致细胞衰老和加速衰老。我们将使用 具体目标如下：(1)研究O-GlcNAc轴加速衰老的分子机制(S) (2)确定O-GlcNAc轴是否调节细胞衰老和 老年小鼠的肝纤维化消退能力；以及(3)测定正常小鼠的代谢和血糖谱。 人肺老化和IPF。完成这些目标将：(A)将O-GlcNAc轴确定为#年的关键枢纽 与衰老相关的代谢失调；(B)显示特定细胞类型上的O-GlcNAc轴 肺脏及其对疾病和加速衰老的易感性和贡献；和(C)证明一个或 在年龄相关性肺疾病IPF中，更多的代谢途径受到O-GlcNAc轴的调节。