Oxidized glutathione regulation of epithelial sodium channels in newborn lung injury

氧化型谷胱甘肽对新生儿肺损伤中上皮钠通道的调节

• 批准号: 10187639
• 负责人: My N. Helms
• 金额: $ 38.47万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10187639
• 关键词: Acute Lung Injury; Adult; Alveolar; Amiloride; Antioxidants; Apical; Attenuated; Back; Binding; Bioinformatics; Biological; Birth; Blood Circulation; C57BL/6 Mouse; Cells; Clinical; Data; Development; Disulfides; Epithelial; Epithelial Cells; Excision; Exposure to; Fetal Lung; Floods; Fluid Balance; Functional disorder; Gases; Glutathione; Glutathione Disulfide; Goals; Health; Hyperoxia; Injury; Investigation; Kinetics; Life; Liquid substance; Lung; Maps; Mass Spectrum Analysis; Measures; Modeling; Molecular; Movement; Mus; Newborn Infant; Organ; Outcome; Oxidation-Reduction; Oxidative Stress; Oxides; Oxygen; Pathogenesis; Patients; Pharmacology; Phenotype; Play; Population; Post-Translational Protein Processing; Premature Infant; Probability; Process; Proteins; Public Health; Reaction; Recycling; Regulation; Research; Research Personnel; Risk; Risk Factors; Role; Signal Pathway; Site-Directed Mutagenesis; Sodium Chloride; Structure; Structure of parenchyma of lung; Sulfhydryl Compounds; Supplementation; Surface; Time; Transmembrane Domain; Water; airway epithelium; base; cell injury; disulfide bond; epithelial Na+ channel; experience; extracellular; improved; in vivo; interest; lung injury; mouse model; patch clamp; postnatal; pulmonary function; pup; sodium channel proteins

Project Summary/Abstract Epithelial sodium channels (ENaC) serve as the rate limiting step in net salt and water removal from the airspace by generating osmotic gradients for subsequent water transport. In the lung, the regulation of ENaC is fine-tuned so that a precise volume of water continually lines the airway epithelium, which keeps the lungs appropriately moist for effective gas exchange. In some patients with lung injury, it is not clear why lung ENaC fails to function. Normal ENaC activity is critically important in preterm infants, since they are born with immature lung, low levels of ENaC protein, and often require oxygen supplementation. In this study, we look at whether oxygen supplementation (hyperoxia) confounds lung injury by turning off ENaC. We use a term mouse model of hyperoxia induced oxidative stress in our studies. Our rationale is that under high oxygen, the antioxidant glutathione is oxidized to its disulfide form, termed GSSG. Our preliminary data indicates that GSSG can alter ENaC function through direct post translational modification of conserved Cys thiols on ENaC, albeit the modified Cys have not been mapped. Whether GSSG modifies ENaC under a biologically relevant model of hyperoxia induced lung injury has not been evaluated. Our goal is to delineate biologically relevant post-translational modification of lung ENaC by GSSG and determine whether lowering lung GSSG levels can improve health outcomes for preterm infants requiring oxygen supplementation.

项目摘要/摘要 上皮钠通道(ENaC)是净盐分和净水从空气中去除的限速步骤 通过为随后的水运输产生渗透梯度。在肺中，ENaC的调节是微调的 因此，精确的水量不断地排列在呼吸道上皮细胞上，从而适当地保持肺部 湿润，有利于有效的气体交换。在一些肺损伤患者中，肺ENaC无法发挥作用的原因尚不清楚。 正常的ENaC活动对早产儿至关重要，因为他们出生时肺不成熟，水平低 ENaC蛋白，经常需要补充氧气。在这项研究中，我们观察氧气是否 补充(高氧)通过关闭ENaC来混淆肺损伤。我们使用了一种术语鼠标模型 在我们的研究中，高氧诱导了氧化应激。我们的理论基础是在高氧条件下，抗氧化剂 谷胱甘肽被氧化成其二硫化物，称为GSSG。我们的初步数据表明GSSG可以改变 通过ENaC上保守的半胱氨酸硫醇的直接翻译后修饰发挥ENAC功能，尽管修饰 CU尚未被映射。GSSG是否在生物相关的高氧模型下修饰ENaC 诱导性肺损伤尚未得到评估。我们的目标是描绘出与生物相关的翻译后 GSSG对肺ENaC的修饰及降低肺GSSG水平能否改善健康 需要补充氧气的早产儿的结局。

项目成果

Oxidized Glutathione Increases Delta-Subunit Expressing Epithelial Sodium Channel Activity in Xenopus laevis Oocytes

• 发表时间: 2020-05
• 期刊: eMedical research
• 作者: Garett J. Grant;Camila Coca;Xing-Ming Zhao;My N. Helms

Regulation of hyperoxia-induced neonatal lung injury via post-translational cysteine redox modifications.

• DOI: 10.1016/j.redox.2022.102405
• 发表时间: 2022-09
• 期刊: REDOX BIOLOGY
• 影响因子: 11.4
• 作者: Zhang, Tong;Day, Nicholas J.;Gaffrey, Matthew;Weitz, Karl K.;Attah, Kwame;Mimche, Patrice N.;Paine, Robert, III;Qian, Wei-Jun;Helms, My N.
• 通讯作者: Helms, My N.

Tumor microenvironment in salivary gland carcinomas: An orchestrated state of chaos.

• DOI: 10.1016/j.oraloncology.2022.105777
• 发表时间: 2022-02
• 期刊: Oral oncology
• 影响因子: 4.8
• 作者: E. Egal;J. Scarini;R. A. de Lima-Souza;L. Lavareze;P. Fernandes;C. Emerick;Mayara Trevizol Gonçalves-Mayara-Trevizol-Gonça

High-mobility group box-1 increases epithelial sodium channel activity and inflammation via the receptor for advanced glycation end products.

高迁移率 group box-1 通过晚期糖基化终产物受体增加上皮钠通道活性和炎症。

• DOI: 10.1152/ajpcell.00291.2019
• 发表时间: 2020
• 期刊: American journal of physiology. Cell physiology
• 作者: Grant,GarettJ;Liou,TheodoreG;Paine3rd,Robert;Helms,MyN
• 通讯作者: Helms,MyN