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.

项目摘要/摘要急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）是最毁灭性的原因之一重症患者死亡。最近，积累的证据表明线粒体醛脱氢酶2（ALDH2）是针对氧化应激介导的损伤的宝贵盾牌。在我们赠款的最后一个循环，同时研究细胞因子信号抑制器1（SOCS-1）的机制预防ALI，我们发现ALDH2活性在SOCS-1过表达的小鼠中恢复。现在，我们的努力集中在ALI/ARDS中的线粒体和线粒体氧化还原调节上。我们以前的研究表明由高氧产生的活性氧（ROS）是导致线粒体损伤的关键因素。基于在大量有关ROS参与ALI的研究中，许多试验针对ROS来治疗ALI和 ARDS。不幸的是，分子不稳定性使ROS具有挑战性的治疗靶标，并用抗氧化剂（靶向ROS）不会纠正线粒体损伤。但是，更多的合理目标可能是稳定的次级ROS中间体，例如4-羟基-2-非纳尔（4-HNE）。 4-HNE，有毒脂质破坏线粒体生物能学的过氧化产物在氧化应激疾病中起因果作用。因此，清除4-HNE并保留重要的线粒体稳态是一种合理的方法开发新疗法。在各种氧化应激介导的损伤的模型中的研究表明， 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知识不断扩展，但缺乏在我们对ALDH2参与ALI和ARDS的理解中。我们假设ALDH2的激活保护通过恢复A-激酶锚蛋白121（AKAP121）水平来抗高氧诱导的ALI（HALI），该水平保持线粒体功能。我们提出以下具体目的来研究我们的假设：目标1：阐明ALDH2失活，SIAH2积累和AKAP121降解的机制。目标2：阐明AKAP121损失增强ALDH2缺乏引起的HALI的机制。目标3：确定ALDH2激活在高氧和传染性ALI模型中的治疗作用。我们提出的研究将在ALI/ARDS发病机理中揭示新的分子靶标（ALDH2），揭示其在生物学上的意义调节AKAP121水平，并解解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）

Resolvins Decrease Oxidative Stress Mediated Macrophage and Epithelial Cell Interaction through Decreased Cytokine Secretion.

DOI：
10.1371/journal.pone.0136755
发表时间：
2015
期刊：
PloS one
影响因子：
3.7
作者：
Cox R Jr;Phillips O;Fukumoto J;Fukumoto I;Tamarapu Parthasarathy P;Mandry M;Cho Y;Lockey R;Kolliputi N
通讯作者：
Kolliputi N

Enhancer of zeste homolog 2 induces pulmonary artery smooth muscle cell proliferation.

DOI：
10.1371/journal.pone.0037712
发表时间：
2012
期刊：
PloS one
影响因子：
3.7
作者：
Aljubran SA;Cox R Jr;Tamarapu Parthasarathy P;Kollongod Ramanathan G;Rajanbabu V;Bao H;Mohapatra SS;Lockey R;Kolliputi N
通讯作者：
Kolliputi N

The role of club cell phenoconversion and migration in idiopathic pulmonary fibrosis.

DOI：
10.18632/aging.101115
发表时间：
2016-11-29
期刊：
Aging
影响因子：
0
作者：
Fukumoto J;Soundararajan R;Leung J;Cox R;Mahendrasah S;Muthavarapu N;Herrin T;Czachor A;Tan LC;Hosseinian N;Patel P;Gone J;Breitzig MT;Cho Y;Cooke AJ;Galam L;Narala VR;Pathak Y;Lockey RF;Kolliputi N
通讯作者：
Kolliputi N

Alda-1 Attenuates Hyperoxia-Induced Acute Lung Injury in Mice.

DOI：
10.3389/fphar.2020.597942
发表时间：
2020
期刊：
Frontiers in pharmacology
影响因子：
5.6
作者：
Sidramagowda Patil S;Hernández-Cuervo H;Fukumoto J;Krishnamurthy S;Lin M;Alleyn M;Breitzig M;Narala VR;Soundararajan R;Lockey RF;Kolliputi N;Galam L
通讯作者：
Galam L

TXNIP shuttling: missing link between oxidative stress and inflammasome activation.