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：
8725260
负责人：
RICHARD Agustin BOND
金额：
$ 5.87万
依托单位：
UNIVERSITY OF HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-15 至 2014-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8725260
关键词：
Abbreviations Accounting Acute Adenylate Cyclase Adrenal Glands Adrenergic Receptor Adrenergic beta-Antagonists Adverse effects Agonist Anti-Asthmatic Agents Anti-Inflammatory Agents Anti-inflammatory Asthma Attenuated Biological Bone Marrow Bone Marrow Transplantation Bronchodilator Agents Candidate Disease Gene Cell Culture System Cells Cellular biology Chemical Sympathectomy Chronic Clinical Coupling Data Development Effectiveness Epinephrine Epithelial Cells Gene Expression Gene Expression Microarray Analysis Genes Genetic Goals Hematopoietic Human Inflammatory Interleukin-13 Knock-out Knockout Mice Lead Leukocytes Ligands Lung MAP Kinase Gene Mediating Methyltransferase Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinases Modeling Molecular Morphology Mucins Mucous body substance Mus Nadolol Pharmaceutical Preparations Pharmacology Phenocopy Phenotype Production Proteins Research Research Personnel Reserpine Role Signal Pathway Signal Transduction Site Smooth Muscle Myocytes Source Sympathectomy Testing Therapeutic Agents Time Transgenic Organisms Transplantation Universities Videoconferences Videoconferencing Walkers Work airway epithelium airway hyperresponsiveness airway inflammation airway obstruction allergic airway inflammation antigen challenge arrestin 2 asthma prevention attenuation base beta-2 Adrenergic Receptors cell type hematopoietic cell transplantation improved loss of function meetings mortality mouse model novel therapeutics overexpression prevent research study respiratory smooth muscle response

项目摘要

DESCRIPTION (provided by applicant): Asthma is characterized by reversible airway obstruction, airway hyperresponsiveness (AHR) and airway inflammation. The medications used for control and acute relief of asthma vary in their effectiveness and may produce serious side effects. Thus, there is a need to develop new and improved medications for asthma. Our research has shown that, unexpectedly, activation of the ¿2AR is necessary for the development of the asthma phenotype produced by antigen challenge or by direct intra-tracheal administration of IL-13. We have also shown that chronic treatment of mouse models of asthma with ¿2AR-inverse agonists produced broad anti- inflammatory effects in the airways, including dramatic changes in airway epithelium mucus production and morphology. These data suggest that ¿2ARs located on the airway epithelium may be a key target for the effect of ¿2AR inverse agonists. Our long-range goal is to determine the mechanism of the proasthamtic effect of ¿2AR signaling. To do this we need to understand the signaling pathways and their sites of action. In this project, we will: Aim 1. Test the hypothesis that an important target of ¿2AR-inverse agonists is the airway epithelium, and determine what components of the asthma phenotype are due to lung parenchymal cells versus hematopoietic cells by using genetically altered mice and bone marrow transplantation experiments. Aim 2. Determine the role of ¿2AR-¿-arrestin-2-MAPK signaling, in mediating the pro-asthmatic effects of the ¿2AR using genetically altered mice and human bronchial airway epithelial cells, and Aim 3. Using pharmacological and genetic 'sympathectomy', as well as bone marrow transplant experiments, determine the cellular source of the epinephrine activating the ¿2AR allowing its various pro-asthmatic effects, and because weeks of treatment required for the anti-asthmatic effect of ¿2AR-inverse agonists, we will perform microarray analysis for gene expression changes as a lead for possible mechanisms of action. This research could lead to safer and more efficacious drugs for the treatment of asthma, and alter our understanding of asthma at a paradigm-shifting level.

描述（由适用提供）：哮喘的特征是可逆气道目标，气道高反应性（AHR）和气道注入。用于控制和急性缓解哮喘的药物的有效性各不相同，可能会产生严重的副作用。那是有必要开发用于哮喘的新药物和改进的药物。我们的研究表明，出乎意料的是，„ 2AR的激活对于通过抗原挑战或直接传播IL-13产生的哮喘表型的发展是必要的。我们还表明，对哮喘的小鼠模型的慢性治疗具有2AR逆激动剂，在气道中产生了广泛的抗炎作用，包括气道上皮粘液产生和形态的急剧变化。这些数据表明，位于气道上皮上的2AR可能是2AR反向激动剂作用的关键目标。我们的远程目标是确定2AR信号传导的原则作用的机制。为此，我们需要了解信号通路及其作用部位。在这个项目中，我们将：目标1。检验以下假设：``2ar抗体激动剂的重要靶标是气道上皮，并确定哮喘表型的哪些成分是由于肺实质细胞而不是肺部实质细胞而引起的。目的2。确定使用遗传改变的小鼠和人支气管气道上皮细胞介导€2AR介导的侵蚀性效应的作用，并使用药物和遗传学的“交感神经切除术”，并确定骨骼元素的实验。它的各种促疾病效应，并且由于2AR抗逆激动剂的抗心律作用所需的数周，我们将对基因表达变化进行微阵列分析，以此作为可能作用机制的领导。这项研究可能会导致治疗哮喘的更安全，更有效的药物，并改变我们在范式转移水平上对哮喘的理解。