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

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

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:
Oxidative Lipidomics Core
氧化脂质组学核心
  • 批准号:
    8643333
  • 财政年份:
    2014
  • 资助金额:
    $ 36.74万
  • 项目类别:

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急性肺损伤和急性呼吸窘迫综合征的治疗
  • 批准号:
    8429041
  • 财政年份:
    2011
  • 资助金额:
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Analysis of extravascular lung water dynamics and exhaustive evaluation of pulmonary epithelial metabolites to establish a novel therapeutic approach for acute lung injury/ acute respiratory distress syndrome
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  • 批准号:
    22592023
  • 财政年份:
    2010
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OBSERVATIONAL STUDY OF ACUTE LUNG INJURY & ACUTE RESPIRATORY DISTRESS SYNDROME
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  • 批准号:
    7603766
  • 财政年份:
    2007
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急性肺损伤和急性呼吸窘迫综合征的治疗
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