Ferroptosis as a Death Mechanism in Lung Injury - Project 2
铁死亡作为肺损伤的死亡机制 - 项目 2
基本信息
- 批准号:10399560
- 负责人:
- 金额:$ 36.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-01-03 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAcute Lung InjuryAcute Respiratory Distress SyndromeAlveolar MacrophagesAnimalsApoptosisApoptoticArachidonate 15-LipoxygenaseBacterial PneumoniaBiological MarkersBrain DiseasesCardiolipinsCell DeathCell Death Signaling ProcessCellsCessation of lifeChronicClinicalComplexCytoprotective AgentDevelopmentEnvironmentEpithelialEpithelial CellsEventEvolutionExposure toHumanHydrogen PeroxideImmuneImmune responseImmunocompromised HostImmunosuppressionImpairmentIndividualInflammationInnate Immune ResponseKidney DiseasesLeadLipid PeroxidationLipidsLiver diseasesLungMembraneMitochondriaModelingMolecularMusOxidation-ReductionOxidative StressOxidesPathogenesisPathogenicityPathway interactionsPatientsPhosphatidylethanolaminePhospholipidsPlayPropertyProtein IsoformsPseudomonas aeruginosaPseudomonas aeruginosa infectionReactionReactive Oxygen SpeciesReportingRespiratory Tract InfectionsRoleSamplingScaffolding ProteinSignal TransductionSignaling MoleculeTestingVirulence FactorsVirulentWorkbasecell injurydesignepithelial injuryglutathione peroxidasein vivoinhibitorlipidomicslung injurymacrophagemortalitynovelnovel therapeutic interventionnovel therapeuticsoxidationpathogenpathogenic bacteriaperoxidationpredictive markerpreventprogramsselenoenzymesmall molecule
项目摘要
In ARDS, bacterial pathogens damage host cells, activate innate immune responses, and create a pro-oxidant
environment leading to cell death via one of the death programs. This Project will focus on a recently described
death program, ferroptosis, realized via Fe-dependent activation of lipid peroxidation under conditions of
deficiency of glutathione peroxidase 4 (GPX4), a seleno-enzyme uniquely capable of reducing phospholipid
hydroperoxides. We identified 15-hydroperoxy-arachidonoyl-phosphatidylethanolamines (15-HOO-AA-PE) as
specific lipid biomarkers of ferroptosis. We also discovered that complexes of 15-lipoxygenase (15LOX) with a
scaffold protein, PEBP1, play the major role in generating 15-HOO-AA-PE signals. We divulged ferroptosis as
a death program of the human pulmonary epithelium. Ferroptosis occurs in alternatively activated macrophages
with low levels of NO•/iNOS, thus causing immuno-suppression. Unexpectedly, we discovered that a common
Gram-negative pathogen, P. aeruginosa – that does not contain polyunsaturated phospholipid oxidation
substrates– expresses 15LOX (pLoxA) which oxidizes host polyunsaturated PE, generates 15-HOO-AA-PE and
causes ferroptosis in epithelial cells and macrophages independently of the endogenous host 15-LOX.
Ferroptosis-inducing pLoxA was detected in clinical P. aeruginosa isolates from ARDS patients. 15-HOO-AA-
PE were identified in the lung samples from severely immuno-compromised patients with ARDS. Thus, we
postulate the existence of a vicious cycle whereby inflammation/oxidative stress driven ferroptosis supported
by endogenous 15-LOX acts as the major contributor to immunosuppression that sets the stage for the
secondary P. aeruginosa infection of immune-impaired lung and further enhancement of ferroptosis by
exogenous bacterial pLoxA. We propose to design and use selective small molecule pLoxA inhibitors, which
will act as anti-ferroptotic agents thus representing new classes of pulmonary protectors. Aim 1 will reveal and
decipher pathogenic mechanisms through which reactions of phospholipid peroxidation catalyzed by isoforms
of endogenous mammalian 15-LOX or exogenous bacterial pLoxA – in conditions of GPX4/GSH deficiency –
lead to accumulation of hydroperoxy-phospholipids in murine lung epithelial cells (MLE) and alveolar
macrophages and establish molecular identity and ferroptotic properties of these products. By using redox
lipidomics we will identify and quantify 15-HOO-AA-PE biomarkers of ferroptosis in vivo using a two-hit model
of immunosuppression. We will also employ iNOS KO animals exposed to P. aeruginosa to reveal the role of
NO• as a regulator of pLoxA-driven AA-PE oxidation and ferroptotic death in the mouse lung vivo. In Aim 2, we
will design and develop selective inhibitors of pLoxA regulating P. aeruginosa-driven ferroptosis in epithelia and
macrophages as a new class of small-molecule cytoprotective agents preventing breach of the barrier and
immunosuppression.
在ARDS中,细菌病原体破坏宿主细胞,激活先天免疫反应,并产生促氧化剂
环境通过死亡程序之一导致细胞死亡。该项目将集中在最近描述的
死亡程序,铁凋亡,通过铁依赖性激活的脂质过氧化作用的条件下实现,
谷胱甘肽过氧化物酶4(GPX 4)缺乏,这是一种独特的能够减少磷脂的硒酶
氢过氧化物。我们鉴定了15-过氧化氢-花生四烯酸-磷脂酰乙醇胺(15-HOO-AA-PE),
铁凋亡的特异性脂质生物标志物。我们还发现,15-脂氧合酶(15 LOX)与一种
支架蛋白PEBP 1在产生15-HOO-AA-PE信号中起主要作用。我们泄露了铁性下垂
人类肺上皮细胞的死亡程序。铁凋亡发生在交替激活的巨噬细胞中
NO·/iNOS水平低,从而引起免疫抑制。出乎意料的是,我们发现,一个共同的
革兰氏阴性病原体,铜绿假单胞菌-不含多不饱和磷脂氧化
底物-表达15 LOX(pLoxA),其氧化宿主多不饱和PE,产生15-HOO-AA-PE,
引起上皮细胞和巨噬细胞中的铁凋亡,与内源性宿主15-LOX无关。
在ARDS患者的临床铜绿假单胞菌分离株中检测到亚铁中毒诱导pLoxA。15-HOO-AA-
在严重免疫功能低下的ARDS患者的肺样本中鉴定出PE。因此我们
假设存在一个恶性循环,炎症/氧化应激驱动的铁凋亡支持
内源性15-LOX作为免疫抑制的主要贡献者,
继发性铜绿假单胞菌感染免疫受损的肺和进一步加强铁凋亡
外源细菌pLoxA。我们建议设计和使用选择性小分子pLoxA抑制剂,
将作为抗铁中毒剂,因此代表了新型的肺保护剂。目标1将揭示和
破译亚型催化的磷脂过氧化反应的致病机制
内源性哺乳动物15-LOX或外源性细菌pLoxA -在GPX 4/GSH缺乏的条件下-
导致过氧化氢磷脂在鼠肺上皮细胞(MLE)和肺泡
巨噬细胞,并建立这些产物的分子身份和铁毒性。通过使用氧化还原
脂质组学,我们将确定和定量15-HOO-AA-PE生物标志物的铁凋亡在体内使用两次击中模型
免疫抑制。我们还将采用暴露于铜绿假单胞菌的iNOS KO动物来揭示
NO·作为pLoxA驱动的AA-PE氧化和小鼠肺内铁中毒死亡的调节剂在目标2中,
将设计和开发pLoxA的选择性抑制剂,调节上皮中铜绿假单胞菌驱动的铁凋亡,
巨噬细胞作为一类新的小分子细胞保护剂,防止屏障破坏,
免疫抑制
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Valerian E Kagan其他文献
Deciphering of mitochondrial cardiolipin oxidative signaling in cerebral ischemia-reperfusion.
- DOI:
10.1038/jcbfm.2014.204. - 发表时间:
2015 - 期刊:
- 影响因子:
- 作者:
Jing Ji;Sophie Baart;Anna S Vikulina;Robert SB Clark;Tamil S Anthonymuthu;Vladimir A Tyurin;Lina Du;Claudette M St Croix;Yulia Y Tyurina;Jesse Lewis;Erin M Skoda;Anthony E Kline;Patrick M Kochanek;Peter Wipf;Valerian E Kagan;Hülya Bayır - 通讯作者:
lya Bayır
Role of coenzyme Q and superoxide in vitamin E cycling.
辅酶 Q 和超氧化物在维生素 E 循环中的作用。
- DOI:
10.1007/978-1-4899-1789-8_20 - 发表时间:
1998 - 期刊:
- 影响因子:0
- 作者:
Valerian E Kagan;Y. Tyurina;Y. Tyurina;Eric Witt - 通讯作者:
Eric Witt
Sensitive and specific fluorescent probing of oxidative stress in different classes of membrane phospholipids in live cells using metabolically integrated cis-parinaric acid.
使用代谢整合的顺式石蜡油酸对活细胞中不同类别的膜磷脂中的氧化应激进行灵敏和特异的荧光探测。
- DOI:
- 发表时间:
1998 - 期刊:
- 影响因子:0
- 作者:
Valerian E Kagan;Vladimir B. Ritov;Y. Tyurina;V. Tyurin - 通讯作者:
V. Tyurin
Direct evidence for antioxidant effect of Bcl-2 in PC12 rat pheochromocytoma cells.
Bcl-2 在 PC12 大鼠嗜铬细胞瘤细胞中抗氧化作用的直接证据。
- DOI:
- 发表时间:
1997 - 期刊:
- 影响因子:3.9
- 作者:
Y. Tyurina;V. Tyurin;Gianfranca Carta;P. Quinn;N. F. Schor;Valerian E Kagan - 通讯作者:
Valerian E Kagan
Reduction of phenoxyl radicals of the antitumour agent etoposide (VP-16) by glutathione and protein sulfhydryls in human leukaemia cells: Implications for cytotoxicity.
人类白血病细胞中谷胱甘肽和蛋白巯基减少抗肿瘤药物依托泊苷 (VP-16) 的苯氧基自由基:对细胞毒性的影响。
- DOI:
- 发表时间:
1996 - 期刊:
- 影响因子:3.2
- 作者:
J. Yalowich;Y. Tyurina;V. Tyurin;William P. Allan;Valerian E Kagan - 通讯作者:
Valerian E Kagan
Valerian E Kagan的其他文献
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{{ truncateString('Valerian E Kagan', 18)}}的其他基金
Therapeutic targeting MDSC-mediated immune suppression in cancer
针对癌症中 MDSC 介导的免疫抑制的治疗
- 批准号:
10340589 - 财政年份:2021
- 资助金额:
$ 36.74万 - 项目类别:
Therapeutic targeting MDSC-mediated immune suppression in cancer
针对癌症中 MDSC 介导的免疫抑制的治疗
- 批准号:
10540357 - 财政年份:2021
- 资助金额:
$ 36.74万 - 项目类别:
Protein-Oxidized Phospholipid Interactions Determine Epithelial Cell Fate and Asthma Control
蛋白氧化磷脂相互作用决定上皮细胞命运和哮喘控制
- 批准号:
10593942 - 财政年份:2020
- 资助金额:
$ 36.74万 - 项目类别:
Selective Inhibitors of Pro-Ferroptotic Lipoxygenases - Next Generation Radiomitigators
促铁死亡脂氧合酶的选择性抑制剂 - 下一代放射减缓剂
- 批准号:
10176413 - 财政年份:2020
- 资助金额:
$ 36.74万 - 项目类别:
Selective Inhibitors of Pro-Ferroptotic Lipoxygenases - Next Generation Radiomitigators
促铁死亡脂氧合酶的选择性抑制剂 - 下一代放射减缓剂
- 批准号:
10408142 - 财政年份:2020
- 资助金额:
$ 36.74万 - 项目类别:
Protein-Oxidized Phospholipid Interactions Determine Epithelial Cell Fate and Asthma Control
蛋白氧化磷脂相互作用决定上皮细胞命运和哮喘控制
- 批准号:
10375454 - 财政年份:2020
- 资助金额:
$ 36.74万 - 项目类别:
The molecular basis of cardiolipin-protein interactions implicated in intrinsic apoptosis
心磷脂-蛋白质相互作用的分子基础涉及内在细胞凋亡
- 批准号:
9342976 - 财政年份:2016
- 资助金额:
$ 36.74万 - 项目类别:
NANOTOX 2014, 7th International Nanotoxicology Congress
NANOTOX 2014,第七届国际纳米毒理学大会
- 批准号:
8718354 - 财政年份:2014
- 资助金额:
$ 36.74万 - 项目类别:
Intra- and extra-cellular signaling by Cardiolipin in Lung injury
肺损伤中心磷脂的细胞内和细胞外信号传导
- 批准号:
8643330 - 财政年份:2014
- 资助金额:
$ 36.74万 - 项目类别:
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