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: 8857527
• 负责人: VISWANATHAN NATARAJAN
• 金额: $ 201.19万
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8857527
• 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 Markers; 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; radiation-induced injury; 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），具有大幅度的血管渗透性增加作为关键 驱动元素提高了发病率和死亡率。不幸的是，目前不存在特定疗法 减轻了阿里和里里出现的不舒服的血管泄漏。该PPG解决了对 这些灾难性的炎症性撒谎伤害的新颖见解，生物标志物和疗法是通过关注 脂质信号介质和血管生成因子，鞘氨酸1-磷酸（S1P），S1P受体（S1PRS）， S1P代谢和S1P类似物的酶。我们的PPG调查团队帮助创建了这个 引人注目的领域通过最初观察到：i）S1P是一种有效的肺部内刺细胞（EC）刺激； ii） S1P是血清中存在的关键EC趋化剂。生病）S1P增强了肺部单层完整性和； iv） Si P是血管渗透性和肺泡洪水的强大体内抑制剂。我们的PPG紧密涉及4 由最先进的核心支持的Intenwoven项目，并将利用系统生物学方法 将鞘脂定义为Ali和Rili病理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，并解决了细胞内S1P在保护中的作用 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 炎性肺损伤中的蛋白质偶联S1PR，并鉴定出新的基于S1P的生物标志物和 ALI涉及的遗传因素。项目＃3调查人员为Ali开发了81p的新颖类似物 治疗并将在肺损伤的鼠模型中评估这种治疗潜力。与阿里相似，有一个 解决电离辐射的不良血管效应的研究很少。项目＃4将重点放在 S1P类似物（单独或与辛伐他汀的结合）在减少鼠模型中的RILI中的潜在作用 并将S1P靶基因与RILI敏感性联系起来。该PPG在一起解决了关键需求（见解， 生物标志物，疗法）在ALI和RILI中促进了药物基因组学和基于SIP的开发 炎性肺损伤的疗法。

项目成果

Sphingosine kinase 1 is required for mesothelioma cell proliferation: role of histone acetylation.

• DOI: 10.1371/journal.pone.0045330
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Kalari S;Moolky N;Pendyala S;Berdyshev EV;Rolle C;Kanteti R;Kanteti A;Ma W;He D;Husain AN;Kindler HL;Kanteti P;Salgia R;Natarajan V
• 通讯作者: Natarajan V

Targeting sphingosine-1-phosphate signaling in lung diseases.

• DOI: 10.1016/j.pharmthera.2016.09.008
• 发表时间: 2016-12
• 期刊: PHARMACOLOGY & THERAPEUTICS
• 影响因子: 13.5
• 作者: Ebenezer, David L.;Fu, Panfeng;Natarajan, Viswanathan
• 通讯作者: Natarajan, Viswanathan

Sphingolipids in Ventilator Induced Lung Injury: Role of Sphingosine-1-Phosphate Lyase.

• DOI: 10.3390/ijms19010114
• 发表时间: 2018-01-01
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Suryadevara V;Fu P;Ebenezer DL;Berdyshev E;Bronova IA;Huang LS;Harijith A;Natarajan V
• 通讯作者: Natarajan V

Sphingolipids in pulmonary fibrosis.

• DOI: 10.1016/j.jbior.2014.09.008
• 发表时间: 2015-01
• 期刊: Advances in biological regulation
• 作者: Huang LS;Natarajan V
• 通讯作者: Natarajan V

Reactive oxygen species at the crossroads of inflammasome and inflammation.

• DOI: 10.3389/fphys.2014.00352
• 发表时间: 2014
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Harijith A;Ebenezer DL;Natarajan V
• 通讯作者: Natarajan V