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: 8079342
• 负责人: VISWANATHAN NATARAJAN
• 金额: $ 236.63万
• 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/8079342
• 关键词: Role; Sphingolipids; Pathobiology; Lung; Injury

DESCRIPTION (provided by applicant): 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 lung 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 endothelial cell (EC) stimulus; ii) S1P is the key EC chemoattractant present in serum; iii) S1P enhances lung EC monolayer integrity and; iv) S1P 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 S1P 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 S1P-based therapies for inflammatory lung injury.

描述（由申请人提供）：急性肺损伤或ALI（由于败血症或呼吸机诱导的肺损伤）和亚急性肺损伤（由于辐射引起的肺损伤（RILI），血管通透性的大幅度增加，这是一种关键元素的促进效率和死亡率的关键元素，目前尚未泄漏。该PPG通过关注脂质信号介质和血管生成因子，鞘氨氨酸1-磷酸盐（S1P），S1P受体（S1P受体），S1P Offer inter of S1P Anteraite Inluce Inluce Inders apper，解决了这些令人沮丧的肺部受伤的新见解，生物标志物和疗法的关键需求。最初的观察结果是：i）S1P是有效的肺内皮细胞（EC）刺激； ii）S1P是血清中存在的关键EC趋化剂； iii）S1P增强了肺EC单层完整性和； iv）S1P是一种强大的体内抑制剂血管渗透性和肺泡洪水的抑制剂。我们的PPG涉及4个紧密插入的项目，这些项目由核心状态支持，并将利用系统生物学方法将鞘脂定义为Ali和Rili病原体生物学的关键调节剂。项目＃1将评估鞘脂代谢基因作为ALI靶标，并解决细胞内S1P在防御肺部炎症和损伤中的作用。项目＃2将提供有关G蛋白偶联S1PR在炎症性肺损伤中的差异作用的新颖信息，并鉴定了基于S1P的新型生物标志物和ALI涉及的遗传因素。项目＃3研究人员已经开发了S1P的新型类似物用于ALI治疗，并将评估肺损伤鼠模型中的这种治疗潜力。与ALI相似，研究了电离辐射的不良血管作用的研究很少。项目＃4将重点关注单独或与辛伐他汀的S1P类似物的潜在作用，在减少鼠模型中的RILI中，并将S1P靶基因与RILI敏感性联系起来。该PPG共同解决了ALI和RILI中的关键需求（见解，生物标志物，疗法），促进了针对炎症性肺损伤的药物基因组学测定和基于S1P的疗法的发展。