Role of Endothelial eNAMPT Secretion and TLR4 Signaling in the ARDS Vascular Endotype
内皮 eNAMPT 分泌和 TLR4 信号传导在 ARDS 血管内型中的作用
基本信息
- 批准号:10440855
- 负责人:
- 金额:$ 23.27万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-05-20 至 2022-08-30
- 项目状态:已结题
- 来源:
- 关键词:2019-nCoVATP-Binding Cassette TransportersAcute Respiratory Distress SyndromeAddressAttenuatedAutomobile DrivingBacterial InfectionsBindingBiological MarkersBlood CirculationBlood VesselsCOVID-19 pandemicCOVID-19/ARDSCell secretionDNA MethylationDataDeubiquitinationDevelopmentDimerizationDissectionDoseEndothelial CellsEndotheliumEventExposure toFDA approvedFRAP1 geneFamily suidaeFunctional disorderGeneticGenomicsHyperoxiaHypoxiaHypoxia Inducible FactorInflammasomeInflammationInflammatoryKnockout MiceLigationLungMechanical StressMechanical ventilationMitogen-Activated Protein KinasesModelingMolecularMonoclonal AntibodiesMusPatternPermeabilityPharmacotherapyPlasmaPre-Clinical ModelPredispositionProductionProteinsRattusRegulationRiskRoleSARS-CoV-2 infectionSeveritiesSignal TransductionSiteSmall Interfering RNAStimulusStructureTLR4 geneTherapeuticTimeUCHL1 geneUbiquitinationVascular PermeabilitiesVentilatorVentilator-induced lung injuryViralcytokinedruggable targetefficacy validationepigenetic regulationextracellularextracellular vesicleshypoxia inducible factor 1lung injurylung vascular inflammationmortalitynew therapeutic targetnicotinamide phosphoribosyltransferasenitrationnovelpre-clinicalpreclinical studypromoterresponsetherapeutic targettranscription factorvascular inflammation
项目摘要
This A1 application is focused on the critical role of extracellular nicotinamide phosphoribosyltransferase
(eNAMPT) in driving lung vascular inflammation and multi-organ endothelial cell (EC) permeability, events that
are central to increasing ARDS mortality and the COVID-19-ARDS vascular endotype. We initially identified
eNAMPT as a novel ARDS and ventilator-induced lung injury (VILI) therapeutic target utilizing genomic–intensive
approaches and cellular and preclinical studies of excessive mechanical stress/VILI. We showed eNAMPT is a
novel ARDS biomarker with plasma eNAMPT levels increasing in response to viral/bacterial infection and expo-
sure to mechanical ventilation. Importantly, utilizing conditional EC–specific NAMPT KO mice, we have recently
shown that EC contributions to ARDS pathobiology includes eNAMPT secretion into the circulation thereby driv-
ing preclinical ARDS inflammatory lung injury and severity. We have shown that eNAMPT produces these inju-
rious effects by functioning as a damage-associated molecular pattern protein (DAMP) and master regulator of
evolutionarily-conserved inflammatory cascades via novel ligation of the Toll–like receptor 4 (TLR4). Our ex-
citing preclinical data in both rat and porcine ARDS/VILI models have validated the efficacy of the eNAMPT-
neutralizing humanized mAb (ALT-100) in reducing eNAMPT- and LPS-induced TLR4 activation and NFκB-
driven cytokine production, lung permeability and inflammatory lung injury. To further interrogate and validate
eNAMPT as a ARDS therapeutic target, Specific Aim #1 will extend prior studies which showed ROS-generating
ARDS stimuli (hypoxia, hyperoxia, mechanical stress, cytokines) to induce NAMPT expression and NAMPT pro-
moter SNPs to significantly increase eNAMPT plasma levels and risk of ARDS mortality (reduced ventilator-free
days, increased ARDS mortality). SA #1 will characterize the role of three key transcription factors (hypoxia-
inducible factors HIF1/2, NRF2), NAMPT and TLR4 promoter SNPs, and DNA methylation sites in genetic/ep-
igenetic regulation of NAMPT and TLR4 promoter activities. As eNAMPT secretion is key to initiation of inflam-
matory cascade activation, SA #2 will mechanistically explore novel regulation of TLR4- and mechanical stress-
stimulated eNAMPT secretion via extracellular vesicle formation, inflammasome activation, and ABC transport-
ers. As treatment with the eNAMPT-neutralizing ALT-100 mAb reversed the dramatic increases in Akt1 nitration,
MAP kinase effector activation, and reduced Akt/mTOR deubiquitination, SA #3 will dissect the structure/function
mechanisms involved in eNAMPT-TLR4 binding and stimulated increases in EC permeability with specific focus
on MAP kinase effector p90rsk, Akt1 nitration, and UCHL1 activity in EC cytoskeletal-driven barrier dysfunction.
Finally, SA #4 will optimize eNAMPT ALT-100 mAb dosing and time of delivery as a therapeutic strategy in
preclinical rat and porcine ARDS/VILI models. The dissection of EC secretion of eNAMPT and eNAMPT/TLR4
participation in ARDS/VILI pathobiology will accelerate ALT-100 mAb development, an actionable strategy to
attenuate inflammatory lung injury, EC permeability and ARDS/VILI mortality.
此A1申请集中于细胞外烟酰胺磷酸核糖基转移酶的关键作用
(eNAMPT)在驱动肺血管炎症和多器官内皮细胞(EC)渗透性中的作用,
是增加ARDS死亡率和COVID-19-ARDS血管内皮型的核心。我们最初发现
eNAMPT作为一种新的ARDS和呼吸机诱导的肺损伤(VILI)治疗靶点,利用基因组密集型
方法和细胞和临床前研究过度机械应力/VILI。我们展示了eNAMPT是一个
新的ARDS生物标志物,血浆eNAMPT水平响应于病毒/细菌感染和暴露而增加,
一定要机械通气。重要的是,利用条件性EC特异性NAMPT KO小鼠,我们最近
表明EC对ARDS病理生物学的贡献包括eNAMPT分泌到循环中,从而驱动-
临床前ARDS炎症性肺损伤及严重程度。我们已经证明,eNAMPT产生这些损伤-
作为一种损伤相关分子模式蛋白(DAMP)和主调节因子,
通过Toll样受体4(TLR 4)的新型连接,进化保守的炎症级联反应。我们的前-
引用大鼠和猪ARDS/VILI模型的临床前数据已经验证了eNAMPT的功效,
中和人源化mAb(ALT-100)降低eNAMPT和LPS诱导的TLR 4活化和NFκB-
驱动的细胞因子产生、肺渗透性和炎性肺损伤。为了进一步询问和验证
eNAMPT作为ARDS治疗靶点,具体目标#1将扩展先前的研究,这些研究显示ROS生成
ARDS刺激(缺氧、高氧、机械应激、细胞因子)诱导NAMPT表达和NAMPT原-
显著增加eNAMPT血浆水平和ARDS死亡率风险(减少无呼吸机
天,增加ARDS死亡率)。SA #1将表征三个关键转录因子的作用(缺氧-
诱导因子HIF 1 α/2 β,NRF 2),NAMPT和TLR 4启动子SNP,以及遗传/表型中的DNA甲基化位点。
NAMPT和TLR 4启动子活性的遗传调控。由于eNAMPT分泌是引发炎症的关键,
炎症级联激活,SA #2将机械地探索TLR 4和机械应力的新调节,
通过细胞外囊泡形成、炎性小体活化和ABC转运刺激eNAMPT分泌-
呃。由于用eNAMPT中和ALT-100 mAb治疗逆转了Akt 1硝化的急剧增加,
MAP激酶效应子激活和Akt/mTOR去泛素化减少,SA #3将剖析结构/功能
参与eNAMPT-TLR 4结合的机制,并刺激EC通透性增加,具有特异性焦点
MAP激酶效应p90 rsk,Akt 1硝化,和UCHL 1活性在EC细胞驱动的屏障功能障碍。
最后,SA #4将优化eNAMPT ALT-100 mAb给药和给药时间作为治疗策略,
临床前大鼠和猪ARDS/VILI模型。内皮细胞分泌eNAMPT和eNAMPT/TLR 4的研究
参与ARDS/VILI病理学研究将加速ALT-100 mAb的开发,这是一项可行的策略,
减轻炎性肺损伤、EC渗透性和ARDS/VILI死亡率。
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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Joe G. N. Garcia其他文献
Lysocardiolipin Acyltransferase (lycat) Is A Novel Candidate Gene In Radiation-Induced Pulmonary Fibrosis
溶心磷脂酰基转移酶 (lycat) 是辐射诱发肺纤维化的新候选基因
- DOI:
- 发表时间:
2011 - 期刊:
- 影响因子:0
- 作者:
B. Mathew;Longshuang Huang;I. Noth;Shwu;N. Kaminski;Yutong Zhao;M. Wade;E. Berdyshev;J. Siegler;J. Jacobson;Ralph R. Weishelbaum;V. Natarajan;Joe G. N. Garcia - 通讯作者:
Joe G. N. Garcia
Endothelial cell myosin light chain kinase (MLCK) regulates TNFα‐induced NFκB activity
内皮细胞肌球蛋白轻链激酶 (MLCK) 调节 TNFα 诱导的 NFκB 活性
- DOI:
- 发表时间:
2005 - 期刊:
- 影响因子:0
- 作者:
R. Wadgaonkar;L. Linz;A. Zaiman;Joe G. N. Garcia - 通讯作者:
Joe G. N. Garcia
acute lung injury by simvastatin 4 in the attenuation of murine β Critical role for integrin
辛伐他汀 4 在减弱小鼠β整合素的关键作用中对急性肺损伤的影响
- DOI:
- 发表时间:
2012 - 期刊:
- 影响因子:0
- 作者:
J. Jacobson;Weiguo Chen;S. Sammani;Sumegha Mitra;Shwu;Joe G. N. Garcia - 通讯作者:
Joe G. N. Garcia
Intracellular interaction of myosin light chain kinase with macrophage migration inhibition factor (MIF) in endothelium
肌球蛋白轻链激酶与内皮巨噬细胞迁移抑制因子(MIF)的细胞内相互作用
- DOI:
- 发表时间:
2005 - 期刊:
- 影响因子:4
- 作者:
R. Wadgaonkar;S. Dudek;A. Zaiman;L. Linz;A. Verin;S. Nurmukhambetova;L. Romer;Joe G. N. Garcia - 通讯作者:
Joe G. N. Garcia
American medical education at a crossroads
美国医学教育正处于十字路口
- DOI:
10.1126/scitranslmed.aaa2039 - 发表时间:
2015 - 期刊:
- 影响因子:17.1
- 作者:
A. Feldman;M. Runge;Joe G. N. Garcia;A. Rubenstein - 通讯作者:
A. Rubenstein
Joe G. N. Garcia的其他文献
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{{ truncateString('Joe G. N. Garcia', 18)}}的其他基金
Preclinical Development of a Novel eNAMPT-Neutralizing mAb for Pulmonary Hypertension
治疗肺动脉高压的新型 eNAMPT 中和单克隆抗体的临床前开发
- 批准号:
10723260 - 财政年份:2022
- 资助金额:
$ 23.27万 - 项目类别:
Preclinical Development of a Novel eNAMPT-Neutralizing mAb for Pulmonary Hypertension
治疗肺动脉高压的新型 eNAMPT 中和单克隆抗体的临床前开发
- 批准号:
10489982 - 财政年份:2022
- 资助金额:
$ 23.27万 - 项目类别:
Targeting the eNAMPT/TLR4 pathway to reduce Inflammatory Bowel Disease severity
靶向 eNAMPT/TLR4 通路以降低炎症性肠病的严重程度
- 批准号:
10771493 - 财政年份:2022
- 资助金额:
$ 23.27万 - 项目类别:
Targeting the eNAMPT/TLR4 pathway to reduce Inflammatory Bowel Disease severity
靶向 eNAMPT/TLR4 通路以降低炎症性肠病的严重程度
- 批准号:
10602227 - 财政年份:2022
- 资助金额:
$ 23.27万 - 项目类别:
eNamptorTM: A Humanized mAb To Reduce the Severity of Radiation Pneumonitis and Fibrosis
eNamptorTM:一种降低放射性肺炎和纤维化严重程度的人源化单克隆抗体
- 批准号:
10011266 - 财政年份:2020
- 资助金额:
$ 23.27万 - 项目类别:
eNamptorTM: A Humanized mAb To Reduce the Severity of Radiation Pneumonitis and Fibrosis
eNamptorTM:一种降低放射性肺炎和纤维化严重程度的人源化单克隆抗体
- 批准号:
10415224 - 财政年份:2020
- 资助金额:
$ 23.27万 - 项目类别:
eNamptorTM: A Humanized mAb To Reduce the Severity of Radiation Pneumonitis and Fibrosis
eNamptorTM:一种降低放射性肺炎和纤维化严重程度的人源化单克隆抗体
- 批准号:
10274779 - 财政年份:2020
- 资助金额:
$ 23.27万 - 项目类别:
Novel Therapeutic Antibody Targeting of Extracellular NAMPT in Ventilator-Induced Lung Injury (VILI)
呼吸机引起的肺损伤 (VILI) 中细胞外 NAMPT 的新型治疗抗体
- 批准号:
10026453 - 财政年份:2019
- 资助金额:
$ 23.27万 - 项目类别:
Novel Involvement of NAMPT and TLR4 in PAH Vascular Remodeling
NAMPT 和 TLR4 在 PAH 血管重塑中的新参与
- 批准号:
10334432 - 财政年份:2019
- 资助金额:
$ 23.27万 - 项目类别:
Novel Involvement of NAMPT and TLR4 in PAH Vascular Remodeling
NAMPT 和 TLR4 在 PAH 血管重塑中的新参与
- 批准号:
10093119 - 财政年份:2019
- 资助金额:
$ 23.27万 - 项目类别:
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