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DUOX1 and Mitochondria in Obese Asthma

肥胖哮喘中的 DUOX1 和线粒体

基本信息

批准号：
9386934
负责人：
ALBERT VAN DER VLIET
金额：
$ 53.24万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-03 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9386934
关键词：
Address Affect Allergens Allergic Allergic inflammation Asthma Biological Chronic Comparative Study Cytokine Activation Data Diet Disease Disease Progression Epidermal Growth Factor Receptor Epithelial Epithelial Cells Extrinsic asthma Glycolysis Homeostasis Human Hydrogen Peroxide Immune response Inflammation Inflammatory Response Interleukin-13 Knockout Mice Left Mediating Mediator of activation protein Metabolic Metabolic Diseases Metaplasia Mitochondria Mucous body substance Mus NADPH Oxidase Nose Obesity Oxidants Oxidation-Reduction Oxidative Stress Pathology Pathway interactions Process Production Pyroglyphidae Reactive Oxygen Species Recruitment Activity Respiratory physiology Risk Factors Role Scheme Severities Signal Transduction Small Interfering RNA Source Structure of respiratory epithelium Testing Thinness airway remodeling allergic airway disease allergic airway inflammation asthmatic base clinically relevant cytokine early onset extracellular human subject mitochondrial dysfunction mouse model response response to injury src-Family Kinases

项目摘要

PROJECT SUMMARY The majority of severe asthmatics in the U.S. are obese, and obesity is a major risk factor for asthma. Both chronic inflammation associated with asthma and metabolic alterations associated with obesity results in increased oxidative stress and altered redox homeostasis, which likely contributes to disease pathology. Our recent studies identified the NADPH oxidase DUOX1, a major enzymatic source of reactive oxygen species (ROS) within the respiratory epithelium, as a mediator of innate type 2 inflammatory responses to allergens and of clinically relevant features of allergic airway disease in a mouse model of allergic asthma. Preliminary studies of human obese allergic asthmatics or mice with diet-induced obesity (DIO) further indicate that obesity is associated with enhanced production of type 2 cytokines (IL-33, IL-13) in response to allergen challenge. Moreover, preliminary data indicate close and reciprocal interactions between airway epithelial DUOX1 and mitochondrial ROS production, which is associated with enhanced redox-mediated activation and mitochondrial translocation of the tyrosine kinases Src and epidermal growth factor receptor (EGFR), and suggests that enhanced DUOX1 activation in combination with altered mitochondrial integrity and function results in worsened redox perturbations in obese asthma. The Specific Aims of this proposal are 1) to determine the effect of obesity on airway DUOX1 expression and activation and its role in innate cytokine responses to allergen challenge; 2) to assess the interactions between DUOX1 and mitochondrial ROS production, ATP production or glycolysis, and the role of mitochondrial targeting of EGFR/Src pathways; and 3) to evaluate the functional importance of DUOX1-mitochondrial interactions in obese allergic airways disease. Collectively, these studies will address how enhanced DUOX1 in combination with mitochondrial dysfunction due to obesity contributes to epithelial redox perturbations and altered epithelial allergen responses, as a critical mechanism of enhanced or immune responses and airway remodeling in obesity-related asthma.

项目总结