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
基本信息
- 批准号:8643330
- 负责人:
- 金额:$ 38.03万
- 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 2018-12-31
- 项目状态:已结题
- 来源:
- 关键词:Acute Lung InjuryAdult Respiratory Distress SyndromeAntibodiesApoptosisApoptoticAutophagocytosisBacteriaBacterial InfectionsBacterial PneumoniaBindingBlood CirculationBlood VesselsCardiolipinsCell DeathCellsDataDevelopmentDiphosphatesDistalEpithelialEpithelial CellsEpitheliumEvolutionHomeostasisHumanImmune responseInfectionInflammationLabelLifeLigand BindingLipidsLiquid substanceLungMediatingMediator of activation proteinMicroinjectionsMitochondriaMolecularMusOuter Mitochondrial MembraneOxidative StressPathogenesisPathway interactionsPatternPhospholipidsPhosphotransferasesPlasmaPneumoniaProtective AgentsProteinsPseudomonas aeruginosaRoleSignal TransductionStaphylococcus aureusStructureTestingTherapeuticTherapeutic InterventionVirulentannexin A5basecell injurycellular imagingcytochrome ccytotoxicdesigninhibitor/antagonistinjuredinnovationliquid chromatography mass spectrometrylung injurynovelnovel therapeutic interventionpathogenperoxidationprotective effectresearch studysmall molecule
项目摘要
Bacterial pneumonia triggers an exuberant host response with excessive inflammation, oxidative stress, and epithelial cell damage culminating in ARDS. At present, therapeutic interventions to treat ARDS remain limited to lung-protective strategies, as newer molecular mechanism-driven therapeutic interventions have not yet emerged. The specific pathways involved in the evolution of epithelial damage remain elusive. In preliminary experiments, we discovered that a mitochondria-specific phospholipid, cardiolipin (CL), is a critical damage signal that produces severe epithelial lung injury. We observed that after bacterial infection of murine lung epithelial cells or mice, CL transmigrates from the inner to the outer mitochondrial membrane where it acts as a novel signal for autophagy of mitochondria, mitophagy. We also showed that bacterial infection induces cytochrome c (cyt c)-mediated CL peroxidation as a pivotal step in apoptosis. Thus peroxidation of externalized CL acts as a molecular switch that triggers the apoptotic machinery. Finally, we demonstrate that CL and oxidized CL (Clox) are released from injured host cells into circulation and act as mitochondria-derived damage associated molecular patterns (DAMP-CL) triggering innate and adaptive immune responses. Our central hypothesis is that bacterial infection stimulates the unmasking and release of mitochondrial Cls that are indispensible intracellular signals in accelerating mitophagy and apoptosis; upon release into circulation, Cls act as DAMP-CL inducing innate and adaptive immune responses. The Specific Aims of the proposed studies are to determine the: 1. Mechanisms and signaling role of CL asymmetry and its collapse in bacterial-induced mitophagy in distal lung epithelia. 2. Molecular pathways of CL peroxidation and the design and application of small-molecule regulators that protect against bacterial¿ induced distal lung epithelial apoptosis. 3. Molecular identity of species of CUCLox as DAMP-CL in circulation. Based on the highly innovative concept that CL is a unique intra- and extra-cellular signal in mitophagy, apoptosis, and innate/adaptive immune responses in pulmonary epithelium, we will explore four new classes of regulators of CL signaling for the development of pulmonary protective drugs
细菌性肺炎引发过度炎症、氧化应激和上皮细胞损伤的旺盛宿主反应,最终导致ARDS。目前,治疗ARDS的治疗性干预措施仍限于肺保护策略,因为新的分子机制驱动的治疗性干预措施尚未出现。参与上皮损伤演变的特定途径仍然难以捉摸。在初步的实验中,我们发现,一个特定的磷脂,心磷脂(CL),是一个关键的损伤信号,产生严重的上皮肺损伤。我们观察到,在细菌感染小鼠肺上皮细胞或小鼠后,CL从线粒体内膜迁移到线粒体外膜,在那里它作为线粒体自噬(mitophagy)的新信号。我们还表明,细菌感染诱导细胞色素c(cyt c)介导的CL过氧化反应,这是细胞凋亡的关键步骤。因此,外部化CL的过氧化作用作为触发凋亡机制的分子开关。最后,我们证明了CL和氧化CL(Clox)从受损的宿主细胞释放到循环中,并作为神经元衍生的损伤相关分子模式(DAMP-CL)触发先天性和适应性免疫反应。我们的中心假设是细菌感染刺激线粒体Cls的暴露和释放,线粒体Cls是加速线粒体自噬和细胞凋亡中不可或缺的细胞内信号;在释放到循环中后,Cls充当诱导先天性和适应性免疫应答的DAMP-CL。拟议研究的具体目的是确定:1. CL不对称性及其崩溃在细菌诱导的远端肺上皮细胞线粒体自噬中的机制和信号作用。2. CL过氧化的分子途径以及保护免受细菌诱导的远端肺上皮细胞凋亡的小分子调节剂的设计和应用。3.循环中CUCLox与DAMP-CL的分子鉴别。基于CL是肺上皮细胞线粒体自噬、细胞凋亡和先天性/适应性免疫反应中独特的细胞内和细胞外信号这一高度创新的概念,我们将探索四类新的CL信号调节剂,用于肺保护药物的开发
项目成果
期刊论文数量(0)
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会议论文数量(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
beta-Carotene. An antioxidant or a target of oxidative stress in cells?
β-胡萝卜素。
- DOI:
- 发表时间:
1998 - 期刊:
- 影响因子:0
- 作者:
Billy W. Day;Stefania Bergamini;Y. Tyurina;Gianfranca Carta;V. Tyurin;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:
$ 38.03万 - 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:
$ 38.03万 - 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:
$ 38.03万 - 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:
$ 38.03万 - 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:
$ 38.03万 - 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:
$ 38.03万 - 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:
$ 38.03万 - 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:
$ 38.03万 - 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:
$ 38.03万 - 项目类别:
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