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Mechanisms of beta-blocker induced improvements in asthma

β-受体阻滞剂改善哮喘的机制

基本信息

批准号：
8091729
负责人：
RICHARD Agustin BOND
金额：
$ 35.31万
依托单位：
UNIVERSITY OF HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-28 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8091729
关键词：
Acute Adrenergic Receptor Adrenergic beta-Antagonists Adverse effects Affect Agonist Allergens Allergic Alternative Therapies Anti-Inflammatory Agents Anti-inflammatory Antigens Asthma Attention Biochemical Cells Chronic Clinical Trials Data Disease Dose Effectiveness Epithelial Epithelium Extracellular Matrix Extrinsic asthma Genes Genetic Genetic Transcription Goals Heart failure Hormones In Vitro Inflammatory Interleukin-13 Knockout Mice Knowledge Lead Leukocytes Lung Lung Inflammation Metaplasia Methods Modeling Morphology Mucins Mucous body substance Mus Nadolol Patients Pharmaceutical Preparations Production Property Role STAT6 gene Secretory Cell Signal Pathway Signal Transduction Signal Transduction Pathway Techniques Testing Therapeutic Agents Therapeutic Effect Tissues Transgenic Organisms Translations Wild Type Mouse airway epithelium airway hyperresponsiveness airway inflammation airway obstruction base cell type design improved in vivo indexing methacholine mouse model respiratory smooth muscle response restoration

项目摘要

Asthma is characterized by airway obstruction, airway hyperresponsiveness (AHR) and airway inflammation. The medications used for control and acute relief of asthma may vary in effectiveness and produce serious side effects. Also, -30% of asthma patients do not achieve optimal control with any of the (SS (/) Quo ¿<0 model of asthma, we have shown that chronic (28 day) administration of 13-blockers decreased AHR and produced broad anti-inflammatory effects, including dramatic changes in airway epithelium: reduced mucous production, improved morphology and increased production of I32ARs. These data suggest that the airway epithelium may be a key target affected by chronic 13-blocker therapy. Also, in a small clinical trial treating 10 mild asthmatics with the non-selective 13-blocker, nadolol, there was a dose-dependent increase in the P020 methacholine that resulted in a change of> two doubling doses in patients treated with 40 mg of nadolol. Our long-range goal is to develop 13-blockers as an alternative therapy for asthma. To make progress towards this translation, we need to understand their mechanisms of action. In this project, we will test the "-w ¿'<v vii' 0.-. v¿, vii hypothesis that 13-blockers influence airway epithelium via 132ARs to exert their therapeutic effects. The scope of the original proposal is reduced and will comprise only those aims in which we have already made progress and will best support the submission of a renewal application: Specifically, we will: (1). Use genetically altered mice to determine the critical cell type affected by 13-blockers in the mouse model of allergic asthma, and (2). Determine the effect of chronic 13-blocker on specific inflammatory signal transduction pathways in airway epithelium grown in vitro, using a variety of genetic and biochemical methods. 3-0 CD- c)' m=3 C)) PHS 398/2590 (Rev. 11/07) Page 3 ¿-m Continuation Format Page o..¿ 32¿ currently used medications. Thus, there is a need to develop new and better medications for asthma. Based on the paradigm shift that occurred with the use of I3AR agonists and antagonists in heart failure, we tested whether chronic (3-blocker administration may be beneficial in asthma. Using a murine antigen driven 3=(n' 0 moo +L' 0p., >_E Off' :.(n ECM (II :.. O-0 o-- (Q' 6C' 0-:

哮喘以气道阻塞、气道高反应性（AHR）和气道炎症为特征。用于控制和急性缓解哮喘的药物可能在效果上有所不同，并产生严重的副作用。此外，-30%的哮喘患者使用任何一种方法都不能达到最佳控制