Molecular Mechanisms of Hyperoxic Lung Injury

高氧性肺损伤的分子机制

基本信息

批准号：
9757807
负责人：
Narasaiah Kolliputi
金额：
$ 33.22万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-01 至 2020-08-04
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9757807
关键词：
4 hydroxynonenal A kinase anchoring protein Acute Lung Injury Address Adult Respiratory Distress Syndrome Affect Alveolar Amino Acids Animal Model Antioxidants Attenuated Binding Bioenergetics Biological CISH gene Cell Respiration Critical Illness Data Development Disease Enzymes Epithelial Cells Event Goals Grant Homeostasis Homologous Gene Human Hyperoxia Impairment Individual Injury Knowledge Lipid Peroxidation Living Standards Lung Lung Inflammation Lysine Mediating Mitochondria Mitochondrial Proteins Modeling Molecular Molecular Target Mus Mutation Oxidation-Reduction Oxidative Stress Pathogenesis Patients Play Reactive Oxygen Species Regulation Research Role Structure of parenchyma of lung Study models Supportive care Therapeutic Time Ubiquitination aldehyde dehydrogenase 1 aldehyde dehydrogenases base cell injury improved lung injury mitochondrial dysfunction novel therapeutics overexpression preservation protein expression restoration therapeutic target therapy development

项目摘要

Project Summary/Abstract 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: Elucidate the mechanism of ALDH2 inactivation, Siah2 accumulation, and AKAP121 degradation. Aim 2: Elucidate the mechanism by which AKAP121 loss potentiates ALDH2 deficiency-induced HALI. Aim 3: Determine the therapeutic role of ALDH2 activation in hyperoxic and infectious ALI models. 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.

项目概要/摘要急性肺损伤 (ALI) 和急性呼吸窘迫综合征 (ARDS) 是最具破坏性的原因之一危重病人的死亡。最近，越来越多的证据表明线粒体醛脱氢酶 2 (ALDH2) 是抵御氧化应激介导损伤的宝贵屏障。期间我们资助的最后一个周期，同时研究细胞因子信号传导抑制因子 1 (SOCS-1) 的机制为了预防 ALI，我们发现 SOCS-1 过表达的小鼠中 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）是引起线粒体损伤的关键因素。基于根据 ROS 参与 ALI 的大量研究，许多试验都以 ROS 为目标来治疗 ALI 和 ARDS。不幸的是，分子不稳定性使得 ROS 具有挑战性的治疗目标，并且用抗- 氧化剂（针对活性氧）不能修复线粒体损伤。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）。 4-HNE，一种有毒脂质破坏线粒体生物能的过氧化产物，在氧化应激疾病中起着因果作用。因此，清除 4-HNE 并保持重要的线粒体稳态是一个合理的方法。新疗法的开发。对各种氧化应激介导的损伤模型的研究表明， ALDH2 是一种强大的内源性酶，可通过清除有效防止氧化应激 4-HNE。尽管我们对 ALDH2 在其他疾病中的功能的了解不断增加，但仍缺乏我们对 ALDH2 参与 ALI 和 ARDS 的理解。我们假设 ALDH2 的激活可以保护通过恢复 A 激酶锚蛋白 121 (AKAP121) 水平来对抗高氧诱导的 ALI (HALI)，保留线粒体功能。我们提出以下具体目标来研究我们的假设：目标 1：阐明 ALDH2 失活、Siah2 积累和 AKAP121 降解的机制。目标 2：阐明 AKAP121 缺失增强 ALDH2 缺陷诱发的 HALI 的机制。目标 3：确定 ALDH2 激活在高氧和感染性 ALI 模型中的治疗作用。我们提出的研究将揭示 ALI/ARDS 发病机制中的新分子靶标 (ALDH2)，揭示其在调节 AKAP121 水平，并破译其与线粒体功能障碍的联系。

项目成果

期刊论文数量（55）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dysregulation of CLOCK gene expression in hyperoxia-induced lung injury.

高氧诱导的肺损伤中 CLOCK 基因表达失调。

DOI：
发表时间：
2014-06-01
期刊：
影响因子：
0
作者：
Lagishetty, Venu;Parthasarathy, Prasanna Tamarapu;Phillips, Oluwakemi;Fukumoto, Jutaro;Cho, Young;Fukumoto, Itsuko;Bao, Huynh;Cox Jr, Ruan;Galam, Lakshmi;Lockey, Richard F;Kolliputi, Narasaiah
通讯作者：
Kolliputi, Narasaiah

ROMO1 links oxidative stress to mitochondrial integrity.

ROMO1 将氧化应激与线粒体完整性联系起来。

DOI：
发表时间：
2015-03
期刊：
影响因子：
0
作者：
Swarnabala, Sri;Gattu, Mrudula;Perry, Brittany;Cho, Young;Lockey, Richard F;Kolliputi, Narasaiah
通讯作者：
Kolliputi, Narasaiah

Does pIgR down-regulation in COPD cause reprogramming of bronchial epithelium?

COPD 中 pIgR 下调是否会导致支气管上皮细胞重编程？