Ceramide-Induced Destruction in Emphysema

神经酰胺诱导的肺气肿破坏

• 批准号: 10306111
• 负责人: Irina Petrache
• 金额: $ 63.92万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10306111
• 关键词: Address; Alveolar; Alveolus; Area; Autophagocytosis; Autophagosome; Blood-Air Barrier; Calcium; Cell Death; Cells; Ceramides; Chronic; Chronic Obstructive Airway Disease; Complex; Coupled; Data; Development; Disinhibition; Endothelial Cells; Ensure; Enzymes; Epithelial Cells; Exposure to; FRAP1 gene; Gases; Gene Expression Regulation; Genomics; Glucosylceramides; Homeostasis; Human; Impairment; Inhalation; Injury; Knowledge; Link; Lipids; Lung; Lysosomes; Maintenance; Mediating; Membrane; Metabolic; Metabolic Control; Metabolism; Modeling; Organelles; Pathogenesis; Pathway interactions; Pharmacology; Process; Proteins; Pulmonary Emphysema; Regulation; Role; Sampling; Signal Transduction; Signaling Protein; Slice; Smoking; Sphingolipids; Sphingosine; Stress; Testing; Transgenic Organisms; Work; cell growth; cell injury; cigarette smoke-induced; cigarette smoking; clinically significant; design; detection of nutrient; experimental study; exposure to cigarette smoke; fitness; functional outcomes; improved; lung injury; lung repair; metabolomics; mouse model; new therapeutic target; novel; novel strategies; pre-clinical; repair model; repaired; restoration; smoking exposure; sphingosine 1-phosphate; three-dimensional modeling; transcription factor

Abstract A hallmark of emphysema is the net loss of cells that form alveolar units required for gas exchange, due to increased injury and impaired cell repair caused by inhalation of cigarette smoking (CS). Our proposal will focus on how to enhance the survival and repair of lung microvascular endothelial cells, which are essential for the maintenance of the alveolo-capillary membrane. To survive stress, injured cells engage a repair process, autophagy, characterized by a sequence of steps (flux) devoted to the lysosomal degradation of damaged proteins and organelles. Despite progress made in linking autophagy with COPD, little is known as to how CS disrupts autophagic flux and approaches to restore its proper function are lacking. We propose to fill this knowledge gap, by elucidating the regulation of lysosomal fitness and autophagic flux by sphingolipid metabolites during homeostasis and CS exposure. We uncovered two sphingolipid rheostats (sphingosine/S1P and ceramide/glucosylceramide) that control the autophagy flux, but are disturbed by CS. We hypothesize that restoration of the sphingolipid rheostat is required to complete lysosomal autophagy and repair cigarette smoke-induced lung microvascular endothelial cell injury and will alleviate emphysema. We will use complementary approaches of human lung primary endothelial cells in 2D and 3D models of repair, including co-cultured with alveolar type II epithelial cells, human precision cut lung slices, and mouse models of CS exposure, to pursue three specific aims. Completion of these aims will fill important knowledge gaps in emphysema pathogenesis, will mechanistically link targeted metabolomics with functional outcomes, and provide potential new targets for treatment of emphysema.

抽象的 肺气肿的标志是由于由于 吸入吸烟（CS）引起的损伤增加和细胞修复受损。我们的建议将 专注于如何增强肺微血管内皮细胞的生存和修复，这对于 维护肺泡毛细血管膜。为了在压力下生存，受伤的细胞会参与修复过程， 自噬的特征是一系列用于损伤的溶酶体降解的步骤（通量） 蛋白质和细胞器。尽管在将自噬与COPD联系起来方面取得了进展，但对于CS的方式知之甚少 干扰自噬的通量和恢复其适当功能的方法。我们建议填补这个 知识差距，通过阐明通过鞘脂的调节溶酶体健身和自噬的调节 稳态和CS暴露期间的代谢产物。我们发现了两个鞘脂的鞘磷酸果实（鞘氨醇/S1P 控制自噬通量但受CS干扰的神经酰胺/葡萄糖基酰胺）。我们假设这一点 需要恢复鞘脂的晶状体溶裂剂才能完成溶酶体自噬和修复香烟 烟雾诱导的肺微血管内皮细胞损伤，并减轻肺气肿。我们将使用 2D和3D修复模型中人类肺原发性内皮细胞的互补方法，包括 与牙槽II型上皮细胞共培养，人类精确切割肺切片和CS的小鼠模型 接触，追求三个具体目标。这些目标的完成将填补重要的知识差距 肺气肿发病机理，将机械化的靶向代谢组学与功能结果联系起来，并将 为治疗肺气肿提供潜在的新目标。