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S-nitrosylation signaling in asthma

哮喘中的 S-亚硝基化信号传导

基本信息

批准号：
10269972
负责人：
JONATHAN S. STAMLER
金额：
$ 30.26万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10269972
关键词：
ADRBK1 gene Acute Adrenergic Agents Affect Agonist Air Movements American Arrestins Asthma Biochemistry Bronchodilator Agents Cardiac Cell surface Cells Chronic Clinical Collaborations Complement Complex Coupled Cysteine Data Development Diagnosis Enzymes Epithelial Cells Event Excision Exhibits Functional disorder G protein coupled receptor kinase G-Protein-Coupled Receptors GTP-Binding Proteins Genetic Glutathione Glutathione Reductase Height Heterotrimeric GTP-Binding Proteins Homeostasis Human Inhalation Injury Intervention Kinetics Knock-in Link Lung Maintenance Mediating Mediator of activation protein Modeling Molecular Molecular Weight Mus Mutant Strains Mice Mutate Mutation Nitric Oxide Nitric Oxide Synthase Oxidation-Reduction Oxidoreductase Pathogenesis Pathology Pathway interactions Patients Pharmaceutical Preparations Phosphorylation Phosphotransferases Physiology Point Mutation Positioning Attribute Post-Translational Protein Processing Proteins Publishing Pulmonary Function Test/Forced Expiratory Volume 1 Regulation Resistance Role S-Nitrosoglutathione S-Nitrosothiols SKIL gene Sampling Signal Pathway Signal Transduction Single Nucleotide Polymorphism Site Smooth Muscle Myocytes Sulfhydryl Compounds System Tachyphylaxis Testing Work airway hyperresponsiveness airway inflammation airway remodeling arrestin 1 arrestin 2 asthma model asthmatic asthmatic patient base bench to bedside beta-2 Adrenergic Receptors beta-arrestin biological systems clinically relevant cohort cost desensitization efficacy testing improved inhibitor/antagonist innovation mortality mouse model patient subsets personalized approach pre-clinical preservation prevent programs protective effect protein function pulmonary function receptor synergism

项目摘要

PROJECT SUMMARY/ABSTRACT Project 1 Asthma afflicts over 7% of Americans and is the result of chronic inflammation of the airways leading to airway remodeling and hyperresponsiveness that impedes air flow. Severe asthma is asthma that remains problematic despite maximal intervention with conventional asthma therapies, and it accounts for the majority of the mortality and cost of asthma. Dysfunction of airway β2-adrenergic receptor (β2AR) signaling contributes to severe asthma pathogenesis, but the precise signaling mechanisms responsible are unclear. While activation of β2AR using inhaled “β-agonist” drugs is a mainstay of acute asthma treatment, overactivation of β2AR is detrimental and can be fatal. Airway β2ARs signal both through heterotrimeric G proteins and through G protein-coupled receptor kinase (GRK)/β-arrestin pathways that also mediate receptor phosphorylation, desensitization, and internalization. Through a long-standing collaboration, the Stamler and Gaston groups have found that airways are regulated by nitric oxide (NO) through S-nitrosylation of thiols to form S-nitrosothiol (SNO), including on cysteine residues in proteins, a post-translational modification that alters protein functions. In addition, SNO forms on low molecular weight thiols, including glutathione to form SNO-glutathione (GSNO). We demonstrated that inhaled GSNO elevates lung protein-SNO and is protective in asthma, identified the enzyme SNO- glutathione reductase (GSNOR) that inactivates GSNO, and demonstrated that mice lacking GSNOR are protected from developing asthma. Since the β2AR can activate NO synthase in the airways to generate NO, there is a need to discover how this promotes endogenous SNO-mediated bronchoprotection. Our recent work has shown that β2AR is S-nitrosylated after activation, and preventing SNO-β2AR with a point mutation augments β2AR signaling. Importantly, mice bearing β2AR with a knock-in of this mutation are protected from developing asthma. We have previously shown that β2AR regulators GRK2 and β-arrestin2 are S-nitrosylated to inhibit their activity to desensitize the β2AR, and mice bearing GRK2-C340S and β-arrestin2-C253S knock-in exhibit heighted β2AR activity and worsened injury in cardiac models. We have begun to test the efficacy of inhaled GSNO to affect bronchorelaxation and improved lung function in patients, and these data and clinical samples uniquely position us to examine the role of S-nitrosylation in regulating the β2AR pathway from bench to bedside. The Central Hypothesis of Project 1 is that the β2AR signaling system is a key target and mediator of SNO-GSNO- GSNOR protective effects in the airways in severe asthma. Our studies will define the role of S-nitrosylation of specific β2AR signaling pathway components in a murine model of asthma, delineate the roles of inhaled GSNO and of GSNO dinitrosylases on β2AR signaling components in murine models of asthma and in human lung primary cells, and demonstrate that inhaled GSNO improves both airway flow and β2-agonist responsiveness in severe asthma. This work complements the clinical aims in Projects 2 and 3 by providing a mechanistic link between NO/GSNO/GSNOR actions and the regulation of β2AR signaling in severe asthma.

项目总结/文摘