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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
这个A1的应用重点是细胞外烟酰胺磷酸核糖转移酶的关键作用 (ENAMPT)在推动肺血管炎症和多器官内皮细胞(EC)通透性方面的作用,事件 是增加急性呼吸窘迫综合征死亡率和新冠肺炎-急性呼吸窘迫综合征血管内型的核心。我们最初确定了 ENAMPT作为一种新的ARDS和呼吸机诱导肺损伤(VILI)的基因组密集治疗靶点 过度机械应力的入路、细胞学和临床前研究/VILI。我们展示了eNAMPT是一个 一种新的ARDS生物标志物,其血浆eNAMPT水平随着病毒/细菌感染和博览会的反应而升高 当然是机械通风。重要的是,利用有条件的EC特异性NAMPT KO小鼠,我们最近已经 研究表明,EC在ARDS病理生物学中的作用包括eNAMPT分泌到循环中,从而驱动血管紧张素转换酶的生成。 ING临床前ARDS炎性肺损伤及严重程度。我们已经证明,eNAMPT产生这些注射- 作为损伤相关分子模式蛋白(DAMP)的Rious效应和 通过新的Toll样受体4(TLR4)的连接,进化保守的炎症级联反应。我们的前任- 引用了大鼠和猪ARDS/VILI模型的临床前数据,证实了eNAMPT- 中和人源化单抗(ALT-100)降低eNAMPT和内毒素诱导的TLR4活化和NF-κB- 驱动细胞因子的产生、肺通透性和炎症性肺损伤。进一步审问和验证 ENAMPT作为ARDS的治疗靶点,特殊目标#1将扩展先前的研究,这些研究表明ROS产生 ARDS刺激(低氧、高氧、机械应激、细胞因子)诱导NAMPT表达和NAMPT前体 更多SNPs显著增加eNAMPT血浆水平和ARDS死亡率(减少无呼吸机 天数,ARDS死亡率增加)。SA#1将描述三个关键转录因子的作用(缺氧- 诱导因子HIF1/2、NAMPT和TLR4启动子SNP,以及Genetic/EP中的DNA甲基化位点 NAMPT和TLR4启动子活性的遗传调控。因为eNAMPT的分泌是启动炎症的关键- 人工级联激活,SA#2将从机械上探索TLR4-和机械应力-的新调节- 通过细胞外小泡形成、炎性小体激活和ABC转运刺激eNAMPT的分泌。 艾尔斯。随着eNAMPT中和ALT-100单抗的处理逆转了Akt1硝化的急剧增加, MAP激酶效应器激活,Akt/mTOR去泛素化减少,SA#3将剖析其结构/功能 ENAMPT-TLR4结合和刺激的EC通透性增加的机制 在EC细胞骨架驱动的屏障功能障碍中,MAP激酶效应器p90rsk、Akt1硝化和UCHL1活性。 最后,SA#4将优化eNAMPT ALT-100单抗的剂量和给药时间,作为一种治疗策略 临床前期大鼠和猪ARDS/VILI模型。ENAMPT和eNAMPT/TLR4对EC分泌的剖析 参与ARDS/VILI病理生物学将加速ALT-100单抗的开发,这是一种可行的战略,以 减轻炎症性肺损伤、EC通透性和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