Ubiquitin mediated Na,K-ATPase degradation

泛素介导的 Na,K-ATP 酶降解

• 批准号: 6776427
• 负责人: ALEJANDRO Pierre COMELLAS
• 金额: $ 5.65万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6776427
• 关键词: CHO cells; adult respiratory distress syndrome; biological signal transduction; enzyme inhibitors; laboratory rat; lung ischemia /hypoxia; lysosomes; proteasome; protein degradation; radiotracer; respiratory epithelium; selenomethionine; sodium potassium exchanging ATPase; transfection; ubiquitin

DESCRIPTION (provided by applicant): Patient with acute respiratory distress syndrome (ARDS) have their airspaces flooded with edema from pulmonary capillaries thus compromising oxygen transfer from the airspaces into the systemic circulation. Recent investigations have demonstrated the importance of active sodium transport and lung edema clearance in the survival of patients with respiratory failure. The Na,K-ATPase regulates edema clearance across the alveolar epithelium. It has been shown that hypoxia inhibits ion transport and impairs lung edema clearance by yet unclear mechanisms. We sought to study whether hypoxia induces Na,K-ATPase degradation in alveolar epithelial cells (AEC) via the ubiquitin/proteasome or lysosomal pathways. Our preliminary data shows that Na,K-ATPase half life is decreased in the presence of hypoxia (1.5% O2) and its degradation is blocked by proteasomal and lysosomal inhibitors. The specific aims of this proposal are Specific aim # 1:To determine whether hypoxia increases Na,K-ATPase degradation via ubiquitin pathway. Specific aim #2: To determine whether hypoxia increases Na,K-ATPase degradation via the lysosome or proteasome system. Specific aim #3: To determine the E-2s and E-3s enzymes involved in the degradation process of the Na,K-ATPase. Completion of the proposed studies will provide novel information on the effects of hypoxia, specifically as it pertains to mechanisms of inhibition and degradation of the Na,K-ATPase as well as pathways of reversal Na,K-ATPase inhibitions, which may be of relevance for the design of novel strategies to increase alveolar fluid clearance in patients with hypoxemic respiratory failure.

描述（由申请人提供）：急性呼吸窘迫综合征（ARDS）患者的气道充斥着肺毛细血管的水肿，从而阻碍了氧气从气道进入体循环。最近的研究表明，活性钠转运和肺水肿清除对呼吸衰竭患者的生存至关重要。Na， k - atp酶调节肺泡上皮水肿清除。已有研究表明，缺氧抑制离子转运并损害肺水肿清除，但机制尚不清楚。我们试图研究缺氧是否通过泛素/蛋白酶体或溶酶体途径诱导肺泡上皮细胞（AEC）的Na， k - atp酶降解。我们的初步数据表明，在缺氧（1.5% O2）的情况下，Na， k - atp酶的半衰期缩短，其降解被蛋白酶体和溶酶体抑制剂阻断。本提案的具体目的是：确定缺氧是否通过泛素途径增加Na， k - atp酶的降解。具体目的#2：确定缺氧是否通过溶酶体或蛋白酶体系统增加Na， k - atp酶的降解。具体目标#3：确定参与Na， k - atp酶降解过程的E-2s和E-3s酶。这些研究的完成将提供关于缺氧影响的新信息，特别是关于Na， k - atp酶的抑制和降解机制以及Na， k - atp酶抑制逆转的途径，这可能与设计新策略有关，以增加低氧性呼吸衰竭患者的肺泡液清除率。