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.

项目摘要 衰老是肺急性和慢性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，衰老的生物学已经迅速发展，还有几个标志 衰老的衰老，包括营养素感应失调，线粒体功能障碍和细胞衰老的衰老 已提出。但是，这些标志如何调节的确切代谢基础 尚未确定寿命/健康范围和加速衰老。 最近的研究表明，衰老与细胞塑性的丧失和持续的成纤维细胞有关 衰老会导致对肺损伤的持续/非分辨纤维化。有趣的是，糖基化 诸如O连接的N-乙酰葡萄糖（O-GLCNAC）修饰等反应已与 代谢/营养和应力响应信号传导，包括AMPK的调节。我们以前报道了 通过改变的葡萄糖利用和代谢，O-GLCNAC转移酶（OGT）调节光滑 与特发性肺动脉高压加速进展相关的肌肉增殖 （IPAH）。 OGT是一种代谢应力“传感器”，负责涉及的蛋白质的O-GLCNAC修饰 在细胞信号，细胞周期，增殖/衰老，线粒体生物能学和营养代谢中。在 另外，OGA（O-GLCNAC水解酶），O-GLCNAC去除酶，参与了这些细胞过程。 O-GlcNAC/OGT/OGA（此后称为O-GLCNAC轴），因此可以调节多个与衰老相关的标志。 O-GlCNAC轴作为代谢传感器和IPF中衰老的代谢传感器的影响， 尚未研究衰老肺的其他疾病。 我们在此提案中要检验的假设是O-GLCNAC信号的改变代谢感应 轴易于细胞衰老和IPF的加速衰老。我们将使用 以下特定目的：（1）研究加速老化的O-GlCNAC轴的分子机制 和IPF中的细胞衰老； （2）确定O-GLCNAC轴是否调节细胞衰老和 老年小鼠纤维化分辨率的能力。 （3）确定正常的代谢组和糖基谱 人类肺老化和IPF。这些目标的完成将：（a）将O-GLCNAC轴确定为关键枢纽 与衰老相关的代谢失调； （b）在特定细胞类型上演示了O-GlCNAC轴 肺及其对疾病和加速衰老的敏感性和贡献； （c）证明一个或 在与年龄有关的肺部疾病中，O-GLCNAC轴调节更多的代谢途径，IPF。