Mechanisms of Beta-blocker Induced Improvements in Asthma

描述（由申请人提供）：哮喘以可逆性气道阻塞、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的效果各不相同，并可能产生严重的副作用。因此，有必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的激活对于由抗原激发或直接气管内给药IL-13产生的哮喘表型的发展是必要的。我们还表明，用¿2ar逆激动剂慢性治疗哮喘小鼠模型在气道中产生广泛的抗炎作用，包括气道上皮粘液生成和形态的显着变化。这些数据表明，位于气道上皮上的¿2AR可能是¿2AR逆激动剂作用的关键靶点。我们的长期目标是确定¿2AR信号的促哮喘作用的机制。要做到这一点，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。验证¿2ar逆激动剂的重要靶点是气道上皮的假设，并通过转基因小鼠和骨髓移植实验确定哮喘表型的哪些成分是由于肺实质细胞而不是造血细胞。目标2。利用转基因小鼠和人支气管气道上皮细胞和Aim 3确定¿2AR- -arrestin-2- mapk信号在介导¿2AR促哮喘作用中的作用。使用药理学和遗传学“交感神经切除”以及骨髓移植实验，确定肾上腺素激活¿2AR的细胞来源，从而使其具有各种促哮喘作用，并且由于¿2AR逆激动剂的抗哮喘作用需要数周的治疗，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领导。这项研究可能会导致更安全、更有效的治疗哮喘的药物，并在一个范式转换的水平上改变我们对哮喘的理解。

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.