Experimental and Computational Assessment of the Role of NOX4 in Mitochondrial Dysfunction Associated with ARDS

NOX4 在 ARDS 相关线粒体功能障碍中作用的实验和计算评估

基本信息

批准号：
10579495
负责人：
SAID H AUDI
金额：
$ 44.57万
依托单位：
MARQUETTE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10579495
关键词：
ATP Synthesis Pathway Acute Respiratory Distress Syndrome Address Animals Apoptotic Automobile Driving Bioenergetics Biological Blood Vessels Calcium Capillary Endothelial Cell Cell Aging Cell Death Cell Proliferation Cell Survival Cell membrane Cell physiology Cells Cessation of life Clinical Complex Computer Models Data Disease Edema Educational process of instructing Electron Transport Endothelial Cells Environment Enzymes Epithelial Cells Exposure to Feedback Filtration Financial Hardship Generations Glycolysis Health Care Costs Hyperoxia Hypoxemia Individual Inflammation Inflammation Mediators Inflammatory Injury Investigation Kinetics Knock-out Knowledge Length of Stay Life Lipopolysaccharides Lung Measures Mediating Membrane Potentials Mitochondria Modeling Molecular Morbidity - disease rate NADPH Oxidase Outcome Oxidative Stress Oxidative Stress Induction Oxygen Pathogenesis Pathway interactions Patients Pattern Play Positioning Attribute Predisposition Process Production Protein Isoforms Publishing Rattus Reactive Oxygen Species Refractory Regional Perfusion Role Source Structure of parenchyma of lung Tissues Vascular Permeabilities Work computerized tools data integration human model improved in vivo indexing lung injury mathematical model mitochondrial dysfunction mitochondrial membrane mortality response sepsis induced ARDS therapeutic target

项目摘要

PROJECT SUMMARY Acute Respiratory Distress Syndrome (ARDS) is a life-threatening disorder characterized by refractory hypox- emia. Inciting lung injury results in damage to pulmonary endothelial and epithelial cells causing vascular hyper- permeability and edema. A wealth of information exists regarding the effect of ARDS on specific cellular pro- cesses, including ample evidence of a key role for oxidative stress in its initiation, with mitochondria as a primary target. However, the sources of reactive oxygen species (ROS) and the mechanisms by which oxidative stress induces mitochondrial dysfunction in ARDS are poorly understood. Furthermore, a mechanistic and quantitative framework for integrating new and existing bioenergetic data acquired at different biological scales to ascertain their functional implications is lacking. Our proposed work addresses these important knowledge gaps. NOX4, an NADPH oxidase isoform, is unique in that its rate of ROS production is dependent on cellular oxygen (O2) concentration. This is important since a primary therapy for patients with ARDS is provision of high fractions of O2, and rat exposure to high fractions of inspired O2 (hyperoxia) is a model of human ARDS. With O2-depend- ent ROS kinetics, NOX4 is a strong candidate to initiate or amplify lung injury. Activation of NOX4 can also increase mitochondrial ROS production and vice-versa, resulting in an apparent crosstalk between these two important ROS sources and a positive feedback cycle. This can lead to mitochondrial damage and release of pro-inflammatory mitochondrial damage-associated molecular patterns, which in turn can stimulate inflammation and cell death, increase vascular permeability, and can ultimately result in edema, a cardinal feature of ARDS. Motivated by our strong preliminary and published data, our overall hypothesis is that NOX4 is an essential driver of oxidative stress that induces mitochondrial dysfunction, and that altered mitochondrial bioenergetics is a key pathway in the pathogenesis of ARDS. Using a powerful combination of vertically integrated experimental approaches, a unique NOX4 knockout (KO) rat model, and two models of human ARDS (hyperoxia and intratra- cheal lipopolysaccharide), our data will address NOX4’s role in oxidative stress and mitochondrial dysfunction that characterize ARDS. A large-scale computational model will provide a quantitative framework for integrating data acquired at different biological scales to ascertain the functional implications of a change in specific mito- chondrial and cytosolic processes altered in ARDS, including those differentially altered between NOX4 KO and WT rats. Thus, the specific aims are to 1) demonstrate the essential role of NOX4-generated ROS in mitochon- drial dysfunction and microvascular hyperpermeability that characterize ARDS, and 2) develop a mechanistic computational model of lung tissue bioenergetics for predicting functional implications of alterations in mitochon- drial processes. The key outcomes are i) a mechanistic and quantitative understanding of the role of NOX4 in modifying mitochondrial function in ARDS, and ii) a comprehensive computational model for integrating bioen- ergetics data and for identifying potential therapeutic targets to protect against ARDS or mitigate its progression.

项目摘要急性呼吸窘迫综合征（ARDS）是一种威胁生命的障碍 EMIA煽动肺肺渗透性和水肿存在大量有关ARD对特定细胞的影响塞斯（Cesses 但是，反应性氧（ROS）的来源和氧化应激的机制 ARDS中诱导的Mitchondrial功能障碍的理解很差。集成在不同生物群中获取新的和现有的生物能数据以确定的框架他们的功能含义缺乏我们的支撑工作解决这些知识差距。 NADPH氧化酶同工型NOX4是独特的，因为ROS产生的速率取决于细胞氧气（O2）浓度。 O2和大鼠暴露于启发的O2（高氧）是人类ARD的模型。 NOX4是Int Ros Kinetics，是Innitation或Amplify Lung Inn的强大候选者。增加Mitchondrial ROS的产生，反之亦然，导致两个之间的明显crostalk 重要的ROS来源和正反馈周期。促炎性线粒体损伤相关的分子模式，进而刺激炎症和细胞死亡，增加血管渗透性，并迅速导致水肿，这是ARDS的主要特征。由我们的鲜明和发布的数据激励诱导线粒体功能障碍的氧化应激驱动器，并且改变了米孔氏菌生化的驱动力是 ARDS的发病机理中的关键途径。方法，独特的NOX4敲除（KO）大鼠模型，以及两个人类ARD的模型（高氧和内部 - CHEAL脂质菌糖），我们的数据将解决氧化应激和线粒体功能障碍的NOLE 这是ards的特征。在不同的生物量表中获取的数据，以确定特定Mito-变化的功能意义含义软骨和细胞性过程在ARDS中发生了变化 WT大鼠。因此，具体的目的是1）表征ARD的Drial功能障碍和微血管高透明性，2）发展机械肺组织生物能学的计算模型，用于预测线形变化的功能实施 Drial过程。修改ARDS中的Mitchondrial功能，ii）一个综合的计算模型，用于整合生物基精神分析数据以及识别潜在的治疗剂以防止ARDS或减轻ARDS是进步。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Biomarkers for Radiation Pneumonitis Using Noninvasive Molecular Imaging.

DOI：
10.2967/jnumed.115.160291
发表时间：
2016-08
期刊：
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
影响因子：
0
作者：
Medhora M;Haworth S;Liu Y;Narayanan J;Gao F;Zhao M;Audi S;Jacobs ER;Fish BL;Clough AV
通讯作者：
Clough AV

Assessment of Protection Offered By the NRF2 Pathway Against Hyperoxia-Induced Acute Lung Injury in NRF2 Knockout Rats.

DOI：
10.1097/shk.0000000000001882
发表时间：
2022-02-01
期刊：
Shock (Augusta, Ga.)
影响因子：
0
作者：
Audi SH;Jacobs ER;Taheri P;Ganesh S;Clough AV
通讯作者：
Clough AV

Protection by Inhaled Hydrogen Therapy in a Rat Model of Acute Lung Injury can be Tracked in vivo Using Molecular Imaging.

DOI：
10.1097/shk.0000000000000872
发表时间：
2017-10
期刊：
Shock (Augusta, Ga.)
影响因子：
0
作者：
Audi SH;Jacobs ER;Zhang X;Camara AKS;Zhao M;Medhora MM;Rizzo B;Clough AV
通讯作者：
Clough AV

Integrated Computational Model of Lung Tissue Bioenergetics.

肺组织生物能学的综合计算模型。

DOI：
10.3389/fphys.2019.00191
发表时间：
2019
期刊：
Frontiers in physiology
影响因子：
4
作者：
Zhang,Xiao;Dash,RanjanK;Clough,AnneV;Xie,Dexuan;Jacobs,ElizabethR;Audi,SaidH
通讯作者：
Audi,SaidH

Lung injury pathways: Adenosine receptor 2B signaling limits development of ischemic bronchiolitis obliterans organizing pneumonia.

DOI：
10.1080/01902148.2017.1286697
发表时间：
2017-03
期刊：
Experimental lung research
影响因子：
1.7
作者：
Densmore JC;Schaid TR;Jeziorczak PM;Medhora M;Audi S;Nayak S;Auchampach J;Dwinell MR;Geurts AM;Jacobs ER
通讯作者：
Jacobs ER