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Role of Endothelial eNAMPT Secretion and TLR4 Signaling in the ARDS Vascular Endotype

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
批准号:
10440855
负责人:
Joe G. N. Garcia
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
项目状态:
已结题
起止时间:
2022-05-20 至 2022-08-30

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中文摘要
翻译
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。随着使用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。
英文摘要
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.
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Preclinical Development of a Novel eNAMPT-Neutralizing mAb for Pulmonary Hypertension
  • 批准号:
    10723260
  • 项目类别:
  • 资助金额:
    $80.9万
  • 财政年份:
    2022
  • 负责人:
    Joe G. N. Garcia
  • 依托单位:
Preclinical Development of a Novel eNAMPT-Neutralizing mAb for Pulmonary Hypertension
  • 批准号:
    10489982
  • 项目类别:
  • 资助金额:
    $25.96万
  • 财政年份:
    2022
  • 负责人:
    Joe G. N. Garcia
  • 依托单位:
Targeting the eNAMPT/TLR4 pathway to reduce Inflammatory Bowel Disease severity
  • 批准号:
    10771493
  • 项目类别:
  • 资助金额:
    $97.52万
  • 财政年份:
    2022
  • 负责人:
    Joe G. N. Garcia
  • 依托单位:
Targeting the eNAMPT/TLR4 pathway to reduce Inflammatory Bowel Disease severity
  • 批准号:
    10602227
  • 项目类别:
  • 资助金额:
    $26.92万
  • 财政年份:
    2022
  • 负责人:
    Joe G. N. Garcia
  • 依托单位:
海外基金