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: 10474541
• 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/10474541
• 关键词: 4 hydroxynonenal; Ablation; Acute; Age; Aging; Aldehydes; Alveolus; American; Attention; Automobile Driving; Bleomycin; Blood Vessels; Cancer cell line; Cell Aging; Cell Cycle Arrest; Cell Proliferation; Cell Respiration; Cells; Ceramides; Cessation of life; 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; fibrotic lung; idiopathic pulmonary fibrosis; improved; in vivo; interest; interstitial; lipid metabolism; lipidomics; oxidative damage; prevent; senescence; success; therapeutic candidate; transcriptomics; uptake; 4 hydroxynonenal; Ablation; Acute; Age; Aging; Aldehydes; Alveolus; American; Attention; Automobile Driving; Bleomycin; Blood Vessels; Cancer cell line; Cell Aging; Cell Cycle Arrest; Cell Proliferation; Cell Respiration; Cells; Ceramides; Cessation of life; 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; fibrotic lung; 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.

抽象的 该提议的重点是理解的挑战，从而改善了治疗 特发性肺纤维化，一种毁灭性的间质性肺疾病，没有有效的治疗。 长期研究了脂质信号传导和代谢的放松​​管制，长期以来一直在肺纤维化中进行研究，指向 可能会影响病理学的鞘脂和神经酰胺途径的变化。最近几年， 人们对肺中衰老细胞作为关键因素的可能作用增加了注意力 驱动肺纤维化。衰老细胞表达炎症因子，包括信号脂质， 这可能会驱动纤维化过程。当前的问题包括为什么衰老细胞积累 这些患者以及如何减轻他们的促炎活性。一个推论是 防止形成衰变细胞，阻塞其脂质信号传导和/或促进其清除率 从肺部可以预防肺纤维化或阻断疾病进展。 重要的是，鞘脂途径与细胞衰老之间可能存在直接联系。 已证明神经酰胺会诱导原本增殖细胞中的衰老。我们的研究有 与脂质过氧化及其醛末期相关，例如4-羟基诺纳尔作为钥匙 加速衰老的介体。转录组，蛋白质组学和脂肪组分析 增殖和衰老肺细胞将用于识别关键衰老因素和网络 这可能指出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，以促进或预防 衰老。最后，我们将检查是否可以使用脂质代谢途径的操纵 增强衰老细胞的清除，从而限制肺纤维化。在这些方面取得了成功 研究，我们预计可以鉴定具有临床试验的候选治疗剂。