Metabolic Landscape of the Aging Lung

衰老肺的代谢景观

• 批准号: 10396072
• 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/10396072
• 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 Pulmonary 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，衰老的生物学研究进展迅速， 包括营养感知失调、线粒体功能障碍和细胞衰老在内的衰老过程， 提出如然而，这些特征如何调节的精确代谢基础 寿命/健康寿命和加速老化尚未确定。 最近的研究表明，衰老与细胞可塑性的丧失和持续的成纤维细胞有关。 衰老导致持续性/非解决性纤维化，以响应肺损伤。有趣的是， 诸如O-连接的N-乙酰葡糖胺（O-GlcNAc）修饰的反应已经整体连接到 代谢/营养和应激反应信号，包括AMPK的调节。我们先前报道 O-GlcNAc转移酶（OGT）通过改变葡萄糖的利用和代谢， 与特发性肺动脉高压加速进展相关的肌肉增生 （IPAH）。OGT是一种代谢应激“传感器”，负责相关蛋白质的O-GlcNAc修饰 在细胞信号传导、细胞周期、增殖/衰老、线粒体生物能量学和营养代谢中。在 此外，OGA（O-GlcNAc水解酶），O-GlcNAc去除酶，参与这些细胞过程。 因此，O-GlcNAc/OGT/OGA（在此称为O-GlcNAc轴）可以调节多种与衰老相关的标志。 O-GlcNAc轴作为IPF中细胞衰老和老化的代谢传感器和调节剂的影响， 以及其他老化的肺部疾病，还没有被研究。 我们的假设是在这个提议中要测试的是，通过O-GlcNAc信号传导改变的代谢感知 轴易导致IPF中的细胞衰老和加速老化。我们将使用 具体目标如下：（1）研究O-GlcNAc轴在加速老化中的分子机制 （2）确定O-GlcNAc轴是否调节细胞衰老， 老年小鼠纤维化消退的能力。和（3）测定正常人的代谢组学和糖组学谱 人肺老化和IPF。（a）确定O-GlcNAc轴为 与衰老相关的代谢失调;（B）证明了在衰老相关的特定细胞类型上的O-GlcNAc轴; 肺及其对疾病和加速衰老的易感性和贡献;以及（c）证明一种或 在年龄相关性肺病IPF中，O-GlcNAc轴调节更多的代谢途径。