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

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

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会议论文数量(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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健康和疾病中的 ATP 结合盒转运蛋白
  • 批准号:
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革兰氏阴性菌中铁摄取 ATP 结合盒转运蛋白(ABC 转运蛋白)的结构和功能研究
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