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.

项目总结