Role of Sphingolipids in the Pathobiology of Lung Injury

鞘脂在肺损伤病理学中的作用

• 批准号: 8264982
• 负责人: VISWANATHAN NATARAJAN
• 金额: $ 233.78万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8264982
• 关键词: Acute Lung Injury; Address; Alveolar; Angiogenic Factor; Automobile Driving; Biological Assay; Biological Markers; Blood Vessels; Cells; Chemotactic Factors; Coupled; Development; Elements; Enzymes; Floods; GTP-Binding Proteins; Gene Targeting; Genes; Genetic; Inflammatory; Injury; Instruction; Ionizing radiation; Link; Lipids; Lung; Lung Inflammation; Mediator of activation protein; Metabolism; Modeling; Morbidity - disease rate; Mus; Pathway interactions; Patients; Pharmacogenomics; Predisposition; Radiation; Research Personnel; Role; Sepsis; Serum; Signal Transduction; Simvastatin; Source; Sphingolipids; Sphingosine-1-Phosphate Receptor; Stimulus; Systems Biology; Therapeutic; Vascular Permeabilities; Ventilator-induced lung injury; analog; base; genetic variant; improved; in vivo; inhibitor/antagonist; insight; lung injury; monolayer; mortality; novel; restoration; sphingosine 1-phosphate

Acute lung injury or ALI (due to sepsis or ventilator-induced lung injury) and subacute lung injury (due to ionizing radiation-induced lung injury (RILI), share profound increases in vascular permeability as a key element driving increased morbidity and mortality. Unfortunately, specific therapies currently do not exist for alleviating the unremitting vascular leak seen in ALI and RILI. This PPG addresses the critical need for novel insights, biomarkers, and therapies in these devasting inflammatory liing injuries via a focus on the lipid signaling mediator and angiogenic factor, sphingosine-1-phosphate (S1P), S1P receptors (S1PRs), enzymes of S1P metabolism and S1P analogues. Our PPG investigative team helped create this remarkable field by making the initial observations that: i) S1P is a potent lung endothial cell (EC) stimulus; ii) S1P is the key EC chemoattractant present in serum; ill) S1P enhances lung EC monolayer integrity and; iv) Si P is a powerful in vivo inhibitor of vascular permeability and alveolar flooding. Our PPG involves 4 tightly intenwoven Projects supported by State of the Art Cores, and will utilize a systems biology approach to define sphingolipids as key modulators of the pathobiology of ALI and RILI. Project #1 will evaluate sphingolipid metabolizing genes as ALI targets and address the role of intracellular S1P in protection against lung inflammation and injury. Project #2 will provide novel information regarding differential roles of the G protein-coupled S1PRs in inflammatory lung injury as well as identify novel S1P-based biomarkers and genetic factors involved in ALI. Project # 3 investigators have developed novel analogues of 81P for ALI treatment and will assess this therapeutic potential in murine models of lung injury. Similar to ALI, there is a paucity of studies addressing the untoward vascular effects of ionizing radiation. Project #4 will focus on the potential role of S1P analogues, alone or in combination with simvastatin, in reducing RILI in murine models and link S1P target genes to RILI susceptibility. Together, this PPG addresses critical needs (insights, biomarkers, therapies) in ALI and RILI facilitating development of pharmacogenomic assays and SIP-based therapies for inflammatory lung injury.

急性肺损伤或 ALI（由于败血症或呼吸机引起的肺损伤）和亚急性肺损伤（由于 电离辐射引起的肺损伤（RILI），血管通透性显着增加是关键 导致发病率和死亡率增加的因素。不幸的是，目前尚不存在针对 缓解 ALI 和 RILI 中出现的持续血管渗漏。该 PPG 满足了以下关键需求： 通过关注这些毁灭性炎症损伤的新见解、生物标志物和疗法 脂质信号传导介质和血管生成因子、1-磷酸鞘氨醇 (S1P)、S1P 受体 (S1PRs)、 S1P 代谢酶和 S1P 类似物。我们的 PPG 调查团队帮助创建了这个 初步观察发现，S1P 是一种有效的肺内皮细胞 (EC) 刺激剂；二） S1P 是血清中存在的关键 EC 趋化剂； ill) S1P 增强肺 EC 单层完整性；四） Si P 是一种强大的体内血管通透性和肺泡充盈抑制剂。我们的PPG紧密涉及4个 intenweld 项目由最先进的核心支持，并将利用系统生物学方法 将鞘脂定义为 ALI 和 RILI 病理学的关键调节剂。项目#1将评估 鞘脂代谢基因作为 ALI 靶点并解决细胞内 S1P 在预防 ALI 中的作用 肺部炎症和损伤。项目 #2 将提供有关 G 的不同角色的新颖信息 蛋白质偶联 S1PR 在炎症性肺损伤中的作用，并鉴定基于 S1P 的新型生物标志物 ALI 涉及遗传因素。项目 # 3 研究人员已开发出治疗 ALI 的 81P 新型类似物 治疗并将在小鼠肺损伤模型中评估这种治疗潜力。与ALI类似，有一个 很少有研究解决电离辐射对血管的不良影响。项目 #4 将重点关注 S1P 类似物单独或与辛伐他汀联合使用在减少小鼠模型中 RILI 方面的潜在作用 并将 S1P 靶基因与 RILI 易感性联系起来。该 PPG 共同解决了关键需求（洞察力、 ALI 和 RILI 中的生物标志物、疗法）促进药物基因组学检测和基于 SIP 的开发 炎症性肺损伤的治疗。