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（由申请人提供）：哮喘的特点是可逆性气道阻塞、气道高反应性（AHR）和气道炎症。用于控制和急性缓解哮喘的药物的有效性各不相同，并且可能产生严重的副作用。需要开发新的和改进的哮喘药物。我们的研究表明，出乎意料的是， ¿ 2AR 对于抗原攻击或直接气管内施用 IL-13 产生的哮喘表型的发展是必需的。我们还表明，对小鼠哮喘模型进行慢性治疗。 2AR-反向激动剂在气道中产生广泛的抗炎作用，包括气道上皮粘液产生和形态的显着变化。 2位于气道上皮上的AR可能是 ¿ 2AR 反向激动剂我们的长期目标是确定 ¿ 的前列腺作用机制。 2AR 信号传导。为此，我们需要了解信号传导途径及其作用位点。在该项目中，我们将：目标 1. 检验 ¿ 的重要靶标这一假设。 2AR-反向激动剂是气道上皮，并通过使用基因改造小鼠和骨髓移植实验来确定哮喘表型的哪些成分是由肺实质细胞与造血细胞引起的。目标 2. 确定 ¿ 2AR-¿ -arrestin-2-MAPK 信号传导，介导 ¿ 的促哮喘作用2AR 使用基因改造的小鼠和人支气管气道上皮细胞，目标 3。使用药理学和遗传“交感神经切除术”以及骨髓移植实验，确定激活肾上腺素的细胞来源 ¿ 2AR 具有多种促哮喘作用，并且由于 ¿ 的抗哮喘作用需要数周的治疗2AR-反向激动剂，我们将对基因表达变化进行微阵列分析，作为可能的作用机制的线索，这项研究可能会带来更安全、更有效的治疗哮喘的药物，并以范式转变的方式改变我们对哮喘的理解。等级。