Molecular Mechanisms of Hyperoxic Lung Injury

高氧性肺损伤的分子机制

• 批准号: 9336482
• 负责人: Narasaiah Kolliputi
• 金额: $ 37.38万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9336482
• 关键词: 4 hydroxynonenal; A kinase anchoring protein; Acute Lung Injury; Address; Adult Respiratory Distress Syndrome; Affect; Alveolar; Animal Model; Antioxidants; Attenuated; Bioenergetics; Biological; CISH gene; Cell Respiration; Cells; Critical Illness; Data; Development; Disease; Enzymes; Epithelial Cells; Goals; Grant; Half-Life; Health; Homeostasis; Homologous Gene; Human; Hyperoxia; Individual; Injury; Knowledge; Lipid Peroxidation; Living Standards; Lung; Lung Inflammation; Mediating; Mitochondria; Modeling; Molecular; Molecular Target; Mus; Mutation; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Patients; Play; Proteins; Reactive Oxygen Species; Regulation; Research; Role; Site; Structure of parenchyma of lung; Supportive care; Therapeutic; Time; Ubiquitination; aldehyde dehydrogenases; base; improved; lung injury; mitochondrial dysfunction; novel therapeutics; overexpression; protein expression; restoration; therapeutic target; therapy development; ubiquitin-protein ligase

 DESCRIPTION (provided by applicant): Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), are among the most devastating causes of fatality in critically ill patients. Recently, accumulating evidence shows that mitochondrial aldehyde dehydrogenase 2 (ALDH2) serves as an invaluable shield against oxidative stress mediated damage. During the last cycle of our grant, while studying the mechanisms by which suppressor of cytokine signaling 1 (SOCS- 1) protects against ALI, we discovered that ALDH2 activity is restored in SOCS-1 overexpressed mice. Now, our efforts focus on mitochondria and mitochondrial redox regulation in ALI/ARDS. Our previous studies indicate that reactive oxygen species (ROS), produced by hyperoxia, are key factors in causing mitochondrial damage. Based on numerous studies of ROS involvement in ALI, many trials have targeted ROS for the treatment of ALI and ARDS. Unfortunately, molecular instability makes ROS challenging therapeutic targets, and treatment with anti-oxidants (which target ROS) does not rectify mitochondrial damage. However, more plausible targets may be the stable secondary ROS intermediates, such as 4-hydroxy-2-nonenal (4-HNE). 4-HNE, a toxic lipid peroxidation product that disrupts mitochondrial bioenergetics, plays a causal role in oxidative stress diseases. Therefore, clearing 4-HNE and preserving vital mitochondrial homeostasis is a logical approach for the development of new therapies. Studies in models of various oxidative stress-mediated injuries, have shown that ALDH2 is a powerful endogenous enzyme that effectively protects against oxidative stress through the clearance of 4-HNE. Despite our expanding knowledge regarding the function of ALDH2 in other diseases, there is a lack in our understanding of ALDH2 involvement in ALI and ARDS. We hypothesize that activation of ALDH2 protects against hyperoxia-induced ALI (HALI) via restoration of A-kinase anchor protein 121 (AKAP121) levels, which preserves mitochondrial function. We propose the following specific aims to investigate our hypothesis: Aim 1: To determine the mechanism by which ALDH2 regulates AKAP121 expression. Aim 2: To determine the mechanism by which AKAP121 loss potentiates ALDH2 deficiency-induced HALI. Aim 3: To determine the therapeutic role of ALDH2 activation in restoration of AKAP121 levels in HALI. Our proposed studies will unveil a new molecular target (ALDH2) in ALI/ARDS pathogenesis, reveal its biological significance in regulating AKAP121 levels, and decipher its connection to mitochondrial dysfunction.

 描述（由申请人提供）：急性肺损伤 (ALI) 和急性呼吸窘迫综合征 (ARDS) 是危重患者死亡的最具破坏性的原因之一。最近，越来越多的证据表明线粒体乙醛脱氢酶 2 (ALDH2) 是导致危重患者死亡的最严重原因。在我们资助的最后一个周期中，我们正在研究细胞因子信号传导抑制因子 1 (SOCS-1) 的预防机制，这是对抗氧化应激介导的损伤的宝贵屏障。 ALI，我们发现 SOCS-1 过度表达的小鼠中 ALDH2 活性得以恢复。现在，我们的工作重点是 ALI/ARDS 中的线粒体和线粒体氧化还原调节。我们之前的研究表明，高氧产生的活性氧 (ROS) 是关键。基于 ROS 参与 ALI 的大量研究，许多试验都以 ROS 为靶点来治疗 ALI 和 ARDS，不幸的是，分子不稳定性使 ROS 成为治疗靶点和抗氧化剂治疗的挑战。然而，更合理的目标可能是稳定的次级 ROS 中间体，例如 4-羟基-2-壬烯醛 (4-HNE)，这是一种破坏线粒体生物能的有毒脂质过氧化产物。因此，清除 4-HNE 并保持重要的线粒体稳态是在各种模型中开发新疗法研究的合理方法。氧化应激介导的损伤表明 ALDH2 是一种强大的内源性酶，可通过清除 4-HNE 有效地防止氧化应激，尽管我们对 ALDH2 在其他疾病中的功能的了解不断增加，但我们对它的了解还很缺乏。 ALDH2 参与 ALI 和 ARDS。我们研究发现 ALDH2 的激活可通过恢复 A 激酶锚蛋白 121 (AKAP121) 来预防高氧诱导的 ALI (HALI)。我们提出以下具体目标来研究我们的假设： 目标 1：确定 ALDH2 调节 AKAP121 表达的机制 目标 2：确定 AKAP121 缺失增强 ALDH2 缺陷诱导的 HALI 的机制。目标 3：确定 ALDH2 激活在恢复 HALI 中 AKAP121 水平方面的治疗作用。我们提出的研究将揭示一个新的分子靶点。 (ALDH2) 在 ALI/ARDS 发病机制中的作用，揭示其在调节 AKAP121 水平方面的生物学意义，并破译其与线粒体功能障碍的联系。