GSNO Reductase, S-Nitrosothiols, and Asthma

GSNO 还原酶、S-亚硝基硫醇和哮喘

基本信息

批准号：
7760105
负责人：
Loretta G Que
金额：
$ 35.1万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-01 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7760105
关键词：
Acute Adrenergic Agents Adult Agonist Allergens Allergic Animals Applications Grants Asthma Breathing Bronchoconstriction Bronchodilator Agents Child Chronic Coupled Cystic Fibrosis Data Disease Enzymes Epithelial Cells Equilibrium G-Protein-Coupled Receptors GTP-Binding Proteins Genetic Genetic Polymorphism Health Homeostasis Human Hypersensitivity Inflammation Liquid substance Literature Lung Lung diseases Mammalian Cell Metabolism Modeling Molecular Weight Mus Muscle Tonus Nitric Oxide Oxidoreductase P-2 Pathogenesis Pathway interactions Patients Phosphotransferases Play Production Proteins Research Personnel Respiratory Failure Rest Role Smooth Muscle Source Tachyphylaxis Testing Tissues Wild Type Mouse adrenergic airway hyperresponsiveness airway obstruction asthmatic airway base cohort desensitization enzyme activity homologous recombination human subject methacholine new therapeutic target programs respiratory smooth muscle response

项目摘要

DESCRIPTION (provided by applicant): In humans, S-nitrosoglutathione (GSNO), an endogenous bronchodilator, is depleted in the airway of asthmatics. GSNO reductase (GSNOR), an enzyme widely expressed across tissues including lung, regulates levels of lung GSNO levels. Wild-type mice develop increased GSNOR activity and decreased lung S-nitrosothiol (SNO) concentration following allergen challenge and suffer from increased airway hypersensitivity. In contrast, mice with a genetic deletion of GSNOR have increased lung SNO levels after allergen challenge and are protected from airway hyperreactivity. GSNOR deficient mice also have lower basal bronchial tone than normal animals and do not desensitize after repeated stimulation with (2 agonist therapy suggesting that endogenous SNOs regulate smooth muscle tone. These results provide genetic evidence in mice that dynamic SNO turnover is a critical mechanism of NO function in health and disease. In this grant application, we will test the hypothesis that depletion of the endogenous bronchodilator, GSNO, from the airway increases airway hyperresponsiveness to methacholine and decreases response to inhaled (2 agonists in human asthma. We will first determine if GSNOR activity is increased in human asthma and correlates with airway SNO expression (Aim 1). We will next determine if GSNOR activity predicts responsiveness to inhaled ((2 agonist therapy and if the presence of polymorphisms of GSNOR predicts enzyme activity, airway SNO concentration, and response to (2 agonists in asthmatic as compared to control subjects (Aim 2). Finally, we plan to determine whether repletion of SNO in subjects with mild asthma confers protection against methacholine induced bronchoconstriction and desensitization to an inhaled (2 agonist (Aim 3). This proposal will further our understanding of GSNOR and SNOs in asthma, how they function as homeostatic agents in asthma, and how repletion of SNO provides a novel therapeutic target.

描述（由申请人提供）：在人类中，内源性支气管扩张剂S-硝基谷硫酸盐（GSNO）在哮喘患者的气道中耗尽。 GSNO还原酶（GSNOR），一种酶，在包括肺在内的组织中广泛表达，调节肺GSNO水平的水平。在过敏原挑战后，野生型小鼠会增加GSNOR活性，并降低肺S-硝基硫醇（SNO）浓度，并且气道超敏反应增加。相比之下，在过敏原挑战后，具有GSNOR遗传缺失的小鼠肺部SNO水平升高，并免受气道高反应性的保护。 GSNOR deficient mice also have lower basal bronchial tone than normal animals and do not desensitize after repeated stimulation with (2 agonist therapy suggesting that endogenous SNOs regulate smooth muscle tone. These results provide genetic evidence in mice that dynamic SNO turnover is a critical mechanism of NO function in health and disease. In this grant application, we will test the hypothesis that depletion of the endogenous bronchodilator, GSNO, from the airway increases airway hyperresponsiveness to methacholine and decreases response to inhaled (2 agonists in human asthma. We will first determine if GSNOR activity is increased in human asthma and correlates with airway SNO expression (Aim 1). We will next determine if GSNOR activity predicts responsiveness to inhaled ((2 agonist therapy and if the presence of polymorphisms of GSNOR预测酶活性，SNO浓度和对（与对照受试者相比的2种激动剂（AIM 2）相比（AIM 2）。最后，我们计划确定在轻度哮喘的受试者中，SNO是否赋予了轻度哮喘的受试者的保护是否可以保护hatacholine诱发的支气管造成的支气管造成的支气管学和降压（2），这是INHALED的（2），这是2 Agonist（2）。哮喘，它们如何充当哮喘中的稳态剂，以及SNO的补充如何提供一种新颖的治疗靶标。