Modulation of Asthma by GSNO-based Therapies

基于 GSNO 的疗法调节哮喘

基本信息

批准号：
9024604
负责人：
Matthew Wolf Foster
金额：
$ 39.25万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-07 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9024604
关键词：
Acute Adrenal Cortex Hormones Aerosols Affect Allergens Anti-Inflammatory Agents Anti-inflammatory Asthma Biochemical Biological Availability Breathing Bronchoconstriction Bronchodilator Agents Cell Culture Techniques Cells Chronic Chronic Disease Development Dexamethasone Disease Donor person Enzymes Epithelial Cells Experimental Models Extrinsic asthma Goals Health Healthcare Hematopoietic Human In Vitro Individual Inflammation Link Lung Lung Transplantation Measures Mediating Metabolism Methods Modality Modeling Molecular Mus NOS2A gene Nitric Oxide Synthase Ovalbumin Oxidoreductase Pathogenesis Pathway interactions Pharmaceutical Preparations Physiological Prevalence Property Protein Isoforms Proteins Proteomics Pyroglyphidae Risk Role S-Nitrosoglutathione S-Nitrosothiols Societies Source Supplementation Therapeutic Toxic effect Treatment Efficacy United States Up-Regulation aerosolized airway hyperresponsiveness airway inflammation airway obstruction airway remodeling asthmatic asthmatic airway base care burden cell type in vivo inhibitor/antagonist methacholine mouse model promoter protein expression response small molecule

项目摘要

DESCRIPTION (provided by applicant): Asthma is a chronic disease characterized by airway inflammation, reversible airway obstruction and airways hyperresponsiveness (AHR). Levels of the endogenous bronchodilator S-nitrosoglutathione (GSNO) are reduced in the airways of asthmatics, and recently, a GSNO-metabolizing enzyme (GSNO reductase; GSNOR) has been identified as a potential modifier of AHR in human asthma. In the lungs of allergen- challenged mice, we observe upregulation of GSNOR and decreased S-nitrosothiols (SNOs), concomitant with increased AHR. We hypothesize that GSNO supplementation via GSNOR inhibition may provide a new avenue for asthma therapy, and in preliminary studies, we have found in mice that inhalation of a small-molecule GSNOR inhibitor (GSNORi) abrogates airway inflammation and protects from allergen-induced AHR. Our specific aims are to: 1) Identify the specific source(s), and levels, of NOS2 that are required for the effects of acute GSNORi administration; 2) Evaluate the therapeutic and potential toxic effects of chronic GSNO/GSNORi versus inhaled corticosteroid (ICS) therapy in a chronic model of HDM challenge; and 3) Identify targets of GSNOR inhibition in primary human airway epithelial cells. Completion of these specific aims will critically advance our understanding of the potential impact and limitations of GSNO- based therapies as acute and chronic treatments for asthma.

描述（由申请人提供）：哮喘是一种慢性疾病，其特征是气道炎症，可逆气道阻塞和气道高反应性（AHR）。内源性支气管扩张剂S-硝基谷硫硫代（GSNO）的水平在哮喘患者的气道中降低，最近，GSNO-Metebolization酶（GSNO还原酶; GSNOR）已被鉴定为人类Asthma中AHR的潜在修饰者。在过敏挑战的小鼠的肺中，我们观察到GSNOR的上调并减少了S-硝基硫醇（SNOS），与AHR的增加有关。我们假设通过GSNOR抑制作用补充GSNO可能会为哮喘治疗提供新的途径，并且在初步研究中，我们发现在小鼠中，吸入小分子GSNOR抑制剂（GSNORI）吸入了气道的炎症，并保护了过敏剂诱导的诱导的AHR。我们的具体目的是：1）确定急性GSNORI给药所需的NOS2的特定来源和水平； 2）在HDM挑战的慢性模型中，评估慢性GSNO/GSNORI与吸入皮质类固醇（ICS）治疗的治疗和潜在毒性作用； 3）确定原发性人类气道上皮细胞中GSNOR抑制的靶标。这些特定目标的完成将严格提高我们对基于GSNO的疗法的潜在影响和局限性的理解，即哮喘的急性和慢性治疗。