Role of Sphingolipids in the Pathobiology of Lung Injury

描述（由申请方提供）：急性肺损伤或ALI（由于脓毒症或呼吸机诱导的肺损伤）和亚急性肺损伤（由于电离辐射诱导的肺损伤（RILI）），血管通透性显著增加，是导致发病率和死亡率增加的关键因素。不幸的是，目前不存在用于减轻ALI和RILI中所见的持续性血管渗漏的特定疗法。该PPG通过关注脂质信号传导介质和血管生成因子、1-磷酸鞘氨醇（S1 P）、S1 P受体（S1 PR）、S1 P代谢酶和S1 P类似物，解决了这些破坏性炎性肺损伤中对新见解、生物标志物和治疗方法的迫切需求。我们的PPG研究团队通过初步观察帮助创建了这一非凡的领域：i）S1 P是一种有效的肺内皮细胞（EC）刺激物; ii）S1 P是血清中存在的关键EC化学引诱物; iii）S1 P增强肺EC单层完整性; iv）S1 P是一种强大的体内血管通透性和肺泡灌流抑制剂。我们的PPG涉及4个紧密交织的项目，由最先进的核心支持，并将利用系统生物学方法来定义鞘脂作为ALI和RILI病理生物学的关键调节剂。项目#1将评估作为ALI靶点的鞘脂代谢基因，并解决细胞内S1 P在保护肺部炎症和损伤中的作用。项目#2将提供关于G蛋白偶联S1 PRs在炎症性肺损伤中的不同作用的新信息，并确定新的基于S1 P的生物标志物和涉及ALI的遗传因素。项目#3研究人员已经开发出用于ALI治疗的新型S1 P类似物，并将在肺损伤的小鼠模型中评估这种治疗潜力。与急性肺损伤相似，目前关于电离辐射对血管的不良影响的研究很少。项目#4将重点关注S1 P类似物单独或与辛伐他汀联合在降低小鼠模型RILI中的潜在作用，并将S1 P靶基因与RILI易感性联系起来。总之，该PPG解决了ALI和RILI的关键需求（见解、生物标志物、治疗），促进了药物基因组学测定和基于S1 P的炎症性肺损伤治疗的开发。

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.