Lipid signaling in cellular senescence and tissue aging

细胞衰老和组织老化中的脂质信号传导

• 批准号: 10263366
• 负责人: Stephen J. Kron
• 金额: $ 35.3万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10263366
• 关键词: 4 hydroxynonenal; Ablation; Acute; Age; Aging; Aldehydes; American; Attention; Automobile Driving; Bleomycin; Blood Vessels; Cancer cell line; Cell Aging; Cell Cycle Arrest; Cell Proliferation; Cell Respiration; Cells; Ceramides; Cessation of life; Cicatrix; Clinical Trials; DNA Damage; Defect; Diagnosis; Diet; Disease; Disease Progression; Exposure to; Fatty acid glycerol esters; Fibroblasts; Fibrosis; Gases; Genetic; Genotoxic Stress; Health; Hydralazine; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Informatics; Interstitial Lung Diseases; Libraries; Link; Lipid Peroxidation; Lipids; Literature; Lung; Lung diseases; Mediator of activation protein; Metabolic Pathway; Metabolism; Methods; Mus; Oils; Oral; Oxidative Stress; Pathology; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Physiology; Population; Process; Prognosis; Proliferating; Proteomics; Pulmonary Fibrosis; Recording of previous events; Research Personnel; Respiratory Failure; Role; Route; Shortness of Breath; Signal Transduction; Smoking History; Sphingolipids; Stress; Systems Analysis; Tissues; Work; aged; candidate identification; cell injury; effective therapy; experience; feeding; idiopathic pulmonary fibrosis; improved; in vivo; interest; interstitial; lipid metabolism; lipidomics; oxidative damage; prevent; senescence; success; therapeutic candidate; transcriptomics; uptake

Abstract This proposal is focused on the challenge of understanding and thus improving treatment for idiopathic pulmonary fibrosis, a devastating interstitial lung disease without effective treatments. Deregulation of lipid signaling and metabolism has long been studied in pulmonary fibrosis, pointing to changes in sphingolipid and ceramide pathways that may impact pathology. In recent years, increased attention has been paid to a possible role for senescent cells in the lung as a critical factor driving pulmonary fibrosis. Senescent cells express inflammatory factors, including signaling lipids, which may drive the fibrotic process. Current questions include why senescent cells accumulate in these patients and how their pro-inflammatory activity might be mitigated. An inference is that preventing formation of senescent cells, blocking their lipid signaling and/or promoting their clearance from the lung might prevent pulmonary fibrosis or block disease progression. Importantly, there may be a direct link between sphingolipid pathways and cellular senescence. Ceramides have been shown to induce senescence in otherwise proliferating cells. Our studies have implicated lipid peroxidation and its aldehyde end-products such as 4-hydroxynonenal as key mediators of accelerated senescence. Transcriptomic, proteomic and lipidomic analysis of proliferative and senescent lung cells will be used to identify key senescence factors and networks that may point to the specific lipid metabolic pathways that drive senescence and inflammatory signaling. We will then examine lipids and modulators for the ability to promote or prevent senescence. Finally, we will examine whether manipulation of lipid metabolic pathways can be used to potentiate clearance of senescent cells and thereby limit pulmonary fibrosis. With success in these studies, we anticipate identification of candidate therapeutics with potential to move to clinical trials.

摘要 该提案的重点是了解并从而改善治疗的挑战， 特发性肺纤维化，一种没有有效治疗的破坏性间质性肺病。 长期以来，人们一直在研究肺纤维化中脂质信号传导和代谢的失调， 鞘脂和神经酰胺途径的变化可能会影响病理学。近年来， 越来越多的注意力已经放在肺中衰老细胞作为关键因素的可能作用上 导致肺纤维化衰老细胞表达炎症因子，包括信号脂质， 这可能会导致纤维化过程目前的问题包括为什么衰老细胞聚集在 这些患者以及如何减轻其促炎活性。一个推论是， 防止衰老细胞的形成，阻断其脂质信号传导和/或促进其清除 可以预防肺纤维化或阻止疾病进展。 重要的是，鞘脂途径和细胞衰老之间可能存在直接联系。 神经酰胺已被证明在其他增殖细胞中诱导衰老。我们的研究 涉及脂质过氧化及其醛类终产物如4-羟基壬烯醛作为关键 加速衰老的介质。转录组、蛋白质组和脂质组学分析 增殖和衰老的肺细胞将被用于识别关键的衰老因子和网络 这可能指向驱动衰老和炎症的特定脂质代谢途径， 信号然后，我们将检查脂质和调节剂的能力，以促进或防止 衰老最后，我们将研究是否可以使用脂质代谢途径的操纵 以增强衰老细胞的清除，从而限制肺纤维化。在这些成功的 研究中，我们预计识别候选疗法有可能进入临床试验。