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

基本信息

项目摘要

In spite of the serious threats of intentional or accidental exposures to radiation, molecular mechanisms of injury after total body irradiation (TBI) are not completely clear, hence radiomitigative approaches remain insufficient. Our discoveries of oxygenated cardiolipins (CLs) as required stages of TBI apoptosis have already resulted in mitochondria-targeted GS-nitroxides and imidazole-substituted fatty acids as anti-apoptotic radiomitigators. Similarly, deciphering the TBI ferroptotic signaling by hydroperoxy-phosphatidylethanolamines (HOO-PEs) produced by 15- lipoxygenases (15LOX) complexes with phosphatidylethanolamine-binding protein 1 (15-LOX/PEBP1) guides us to new inhibitors as novel radiomitigators. Our demonstration of “theft- ferroptosis” by a bacterial pathogen, Pseudomonas aeruginosa, utilizing its 15-LOX (pLoxA) (12) to trigger ferroptosis of the host (epithelial) cells indicates that TBI induced non-sterile inflammation may be also therapeutically targeted. Our central hypothesis is that radiation triggered responses engage several types of programmed necrotic death, particularly ferroptosis, in GI epithelial cells and the major innate immune cells, neutrophils and macrophages, evolving over time and driving necro-inflammatory vs pro-resolving apoptotic responses during sterile and non-sterile inflammation and culminating in multiple organ dysfunction and mortality. This sets the stage for a principally new understanding of the TBI mechanisms and leads to a new harmonized radiomitigation strategy of time- and mechanism-specific targeting of the leading cell death pathways. Our hypothesis will be tested as follows: Aim 1: By employing Redox Lipidomics identify specific oxygenated phospholipid signatures of the major death programs in epithelial cells, neutrophils and macrophages of the GI of irradiated mice at different stages of sterile and non-sterile necro-inflammation. These newly discovered TBI lipid biomarkers will be related to: i) specific protein markers of cell death, ii) major pro- and anti-inflammatory lipid mediators, iii) cytokines, and iv) breach of the epithelial barrier and immunosuppression. Aim 2: Explore molecular mechanisms of sensitivity/resistance to ferroptosis of macrophages and neutrophils polarized to M1 (N1) and M2 (N2) states in response to pro-/anti-inflammatory conditions and expression of 15LOX and iNOS/NO• system in vitro and TBI induced ferroptosis in vivo. We will employ 15LOX and iNOS KO mice and also quantitatively assess the role of P. aeruginosa and its pLoxA in gut ferroptosis and radiosensitivity of mice to TBI. Aim 3: Design new selective inhibitors of pro-ferroptotic catalytic activity of mammalian 15LOX as well as prokaryotic pLoxA of P. aeruginosa and test them as anti-ferroptotic radiomitigators during sterile and non-sterile stages of TBI radiation disease. Overall, this project is based on an entirely new concept that abandons the search for a single “silver-bullet” radiomitigator and includes a harmonized combination of several mitigators controlling TBI triggered aberrant reactions in time- and mechanism-dependent manner.
尽管受到故意或意外辐射的严重威胁,但在发生辐射后损伤的分子机制 全身照射(TBI)尚不完全清楚,因此放射增敏方法仍然不足。我们的 氧合心磷脂(CLS)作为脑损伤细胞凋亡所需阶段的发现已经导致了 线粒体靶向GS-氮氧化物和咪唑取代脂肪酸作为抗凋亡放射增强剂。同样, 用15-羟基磷脂酰乙醇胺产生的羟基过氧磷脂酰乙醇胺(HO-PE)破译TBI铁链信号 脂氧合酶(15LOX)与磷脂酰乙醇胺结合蛋白1(15-LOX/PEBP1)的复合体引导我们 作为新型放射增强剂的新型抑制剂。我们通过一种细菌病原体演示了“偷窃-铁下垂”, 铜绿假单胞菌,利用其15-LOX(PLoxA)(12)触发宿主(上皮)细胞的铁性下垂 脑外伤引起的非无菌炎症也可能是治疗的靶点。我们的中心假设是辐射 在胃肠道上皮细胞中,触发的反应涉及几种类型的程序性坏死性死亡,特别是铁性下垂 和主要的先天免疫细胞,中性粒细胞和巨噬细胞,随着时间的推移而进化,并推动坏死性炎症 VS在无菌和非无菌炎症和最终导致多器官死亡期间的促凋亡反应 功能障碍和死亡率。这为从根本上对TBI机制的新理解奠定了基础,并导致了 一种针对主要细胞死亡的时间和机制特异性靶向的新的协调放射治疗策略 小路。我们的假设将被检验如下:目标1:通过使用氧化还原脂质组学识别特定的 猪上皮细胞、中性粒细胞和巨噬细胞主要死亡程序的氧合磷脂特征 无菌和非无菌坏死性炎症不同阶段受照小鼠的胃肠道指数。这些新发现的TBI 脂质生物标志物将与:i)细胞死亡的特定蛋白质标志物,ii)主要的促炎和抗炎脂质有关 三是细胞因子,四是突破上皮屏障和免疫抑制。目标2:探索分子 巨噬细胞和中性粒细胞对M1(N1)和M2(N2)极化的铁下垂敏感/抵抗机制 促/抗炎状态及15LOX和iNOS/NO·系统在体外和 在体脑损伤诱导的铁性下垂。我们将使用15LOX和iNOS KO小鼠,并定量评估 铜绿假单胞菌及其pLoxA对小鼠肠道铁性下垂及其放射敏感性的影响。目标3:设计新的精选产品 哺乳动物15LOX和原核铜绿假单胞菌pLoxA铁链酶原催化活性的抑制物 在TBI放射病的无菌和非无菌阶段测试它们作为反铁上链放射促进剂的作用。总体而言,这 该项目基于一种全新的概念,即放弃寻找单一的“银弹”放射发射器,并 包括几种缓释剂的协调组合,可及时控制TBI触发的异常反应-以及 机制依赖的方式。

项目成果

期刊论文数量(0)
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Valerian E Kagan其他文献

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
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
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:
    10540357
  • 财政年份:
    2021
  • 资助金额:
    $ 40.88万
  • 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:
    10340589
  • 财政年份:
    2021
  • 资助金额:
    $ 40.88万
  • 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:
    $ 40.88万
  • 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:
    $ 40.88万
  • 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:
    $ 40.88万
  • 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:
    $ 40.88万
  • 项目类别:
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
  • 批准号:
    10399560
  • 财政年份:
    2014
  • 资助金额:
    $ 40.88万
  • 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:
    $ 40.88万
  • 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:
    $ 40.88万
  • 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:
    $ 40.88万
  • 项目类别:

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Development of small molecule inhibitors as anti-inflammatory agents and antidotes for arsenicals
开发作为抗炎剂和砷解毒剂的小分子抑制剂
  • 批准号:
    10727507
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    2023
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抗炎药的合成及其构效关系研究
  • 批准号:
    496858-2016
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    2016
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    University Undergraduate Student Research Awards
NAAA Inhibitors as Anti-inflammatory Agents, Phase II
NAAA 抑制剂作为抗炎剂,II 期
  • 批准号:
    9201955
  • 财政年份:
    2015
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    $ 40.88万
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Novel flavonoids as anti-inflammatory agents in alcoholism
新型黄酮类化合物作为酒精中毒的抗炎剂
  • 批准号:
    8251289
  • 财政年份:
    2014
  • 资助金额:
    $ 40.88万
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TLR-7 Agonists as Targeted Anti-inflammatory Agents in Arthritis
TLR-7 激动剂作为关节炎的靶向抗炎药
  • 批准号:
    8302750
  • 财政年份:
    2012
  • 资助金额:
    $ 40.88万
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Design and in vivo delivery of novel anti-inflammatory agents
新型抗炎剂的设计和体内递送
  • 批准号:
    267940
  • 财政年份:
    2012
  • 资助金额:
    $ 40.88万
  • 项目类别:
    Operating Grants
Development of inlammasome inhibitors to be used as anti-inflammatory agents
开发用作抗炎剂的inlammasome抑制剂
  • 批准号:
    8403458
  • 财政年份:
    2012
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    $ 40.88万
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TLR-7 Agonists as Targeted Anti-inflammatory Agents in Arthritis
TLR-7 激动剂作为关节炎的靶向抗炎药
  • 批准号:
    8472443
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    2012
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    $ 40.88万
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Development of inlammasome inhibitors to be used as anti-inflammatory agents
开发用作抗炎剂的inlammasome抑制剂
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    8549297
  • 财政年份:
    2012
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    $ 40.88万
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