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Parkin in mitochondrial dysfunction and airway inflammation of obese asthma

Parkin 在肥胖哮喘线粒体功能障碍和气道炎症中的作用

基本信息

批准号：
10264924
负责人：
Hong W Chu
金额：
$ 73.14万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-16 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10264924
关键词：
Address Adrenal Cortex Hormones Allergens Arginine Asthma Attenuated Basic Science Biological Availability Bronchoalveolar Lavage Fluid CCL26 gene CRISPR/Cas technology Cell Culture Techniques Clinical Disease Eotaxin Epithelial Cells Equilibrium Exposure to Gene Activation Goals High Fat Diet Human Inflammation Inhalation Interferon Type II Interferons Interleukin-13 Knock-out Liquid substance Lung Measures Mediating Mitochondria Mitochondrial DNA Mus N,N-dimethylarginine Neutrophil Infiltration Nitric Oxide Nitric Oxide Synthase Obesity PINK1 gene Palmitic Acids Pathogenesis Production Public Health Reactive Oxygen Species Research Research Personnel Respiration Role STAT1 gene STAT6 gene Sampling Saturated Fatty Acids Scientist Serum Signal Pathway Signal Transduction Slice Stimulator of Interferon Genes TBK1 gene Testing Thinness Transcription Repressor Translational Research Up-Regulation airway epithelium airway inflammation asthmatic asthmatic airway bronchial epithelium chemokine cytokine eosinophil eosinophilic inflammation experience inhibitor/antagonist innovation interleukin-13 receptor mitochondrial dysfunction mouse model multidisciplinary neutrophil nitrosative stress novel parkin gene/protein response therapeutic evaluation ubiquitin-protein ligase

项目摘要

Project Summary/Abstract The goal of this R01 application is to determine the mechanisms by which mitochondrial dysfunction in obese asthma exacerbates airway inflammation. Nearly 40% of asthmatics in the U.S. are obese. Obese (vs. lean) asthmatics experience more frequent exacerbations, poorer response to inhaled corticosteroids and worse asthma control. There is an unmet need to study the novel pathogenesis of obese asthma. We have found mitochondrial dysfunction in obese asthma airway epithelium, including increased respiration, glycolytic rates, reactive oxygen species, and greater numbers of dysfunctional mitochondria. We discovered up-regulation of Parkin (Park2) in obese asthma airway epithelium. Parkin is an E3 ubiquitin ligase that regulates mitophagy by degrading defective mitochondria. We further observed increased levels of mitochondrial DNA (mtDNA) and palmitic acid (PA) levels in obese asthma bronchoalveolar lavage fluid and serum samples. Moreover, type 2 cytokine IL-13, type 1 cytokine IFN-g and palmitic acid (PA, a saturated fatty acid increased in obese asthma) increased airway epithelial Parkin levels. Parkin is essential to IL-13-mediated mtDNA release and airway neutrophilic and eosinophilic inflammation in mice and in human airway epithelial cells. We hypothesize that Parkin is up-regulated in obese asthma airways with dysfunctional mitochondria, which is amplified by the type 1 or type 2 cytokine milieu, enhancing mitochondrial DNA release and exaggerating airway inflammation. In Aim 1, we will determine the mechanisms by which Parkin is up-regulated in obese asthma by measuring Parkin, PA, mitophagy, type 1 and type 2 cytokines, and nitric oxide (NO), and performing human airway epithelial cell and precision-cut lung slice cultures to determine if IFN-g, IL-13 and PA increase Parkin in part by reducing transcriptional repressor THAP11. We then test if restoring NO bioavailability reduces Parkin activity. In Aim 2, we will determine how Parkin enhances airway mtDNA release and neutrophilic inflammation. By using Parkin, TLR9 and STAT1 knockout human airway epithelial culture and mouse models, we will test if excessive Parkin in a type 1 cytokine setting of obese asthma promotes mtDNA release, and amplifies neutrophilic inflammation through the TLR9/STAT1 signaling axis. In Aim 3, we will determine the mechanisms by which Parkin enhances airway eosinophilic inflammation. We will test if Parkin-mediated mtDNA release in a type 2 cytokine setting amplifies STAT6 signaling and pro-eosinophilic cytokine (e.g. eotaxin) production. Research findings from our proposed studies will likely provide several key targets (e.g. Parkin, TLR9) to treat obese asthma, a heterogenous disease currently without specific therapies.

项目总结/文摘