DUOX1 and Mitochondria in Obese Asthma

项目摘要 在美国，大多数严重哮喘患者都是肥胖的，肥胖是哮喘的主要危险因素。两 与哮喘相关的慢性炎症和与肥胖相关的代谢改变导致 增加的氧化应激和改变的氧化还原稳态，这可能有助于疾病病理学。我们 最近的研究确定了NADPH氧化酶DUOX 1，它是活性氧的主要酶源 (ROS)在呼吸道上皮内，作为对过敏原的先天性2型炎症反应的介质， 过敏性哮喘小鼠模型中过敏性气道疾病的临床相关特征。初步研究 人类肥胖过敏性哮喘患者或饮食诱导肥胖（DIO）小鼠的研究进一步表明，肥胖是 与2型细胞因子（IL-33、IL-13）的产生增加有关。 此外，初步数据表明，气道上皮DUOX 1和DUOX 2之间存在密切的相互作用。 线粒体ROS的产生，这与增强的氧化还原介导的活化和线粒体 酪氨酸激酶Src和表皮生长因子受体（EGFR）的易位，并表明， 增强的DUOX 1活化与改变的线粒体完整性和功能相结合导致恶化的 肥胖性哮喘的氧化还原紊乱该提案的具体目的是：1）确定肥胖的影响 对气道DUOX 1表达和活化及其在过敏原激发的先天性细胞因子应答中的作用; 2） 为了评估DUOX 1与线粒体ROS产生、ATP产生或糖酵解之间的相互作用， 以及EGFR/Src通路的线粒体靶向作用;以及3）评估 肥胖过敏性气道疾病中DUOX 1-线粒体相互作用总的来说，这些研究将解决如何 增强的DUOX 1与肥胖引起的线粒体功能障碍相结合有助于上皮细胞的氧化还原 干扰和改变的上皮过敏原反应，作为增强或免疫的关键机制， 肥胖相关哮喘的气道反应和气道重塑。

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.