Mechanisms of Beta-blocker Induced Improvements in Asthma

描述（由申请人提供）：哮喘的特征是可逆性气道阻塞、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，并可能产生严重的副作用。因此，需要开发新的和改进的哮喘药物。我们的研究已经表明，出乎意料的是，通过抗原激发或通过直接气管内给予IL-13产生的哮喘表型的发展需要Δ 2AR的激活。我们还表明，用2AR-反向激动剂长期治疗哮喘小鼠模型在气道中产生广泛的抗炎作用，包括气道上皮粘液产生和形态的显著变化。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靶点。我们的长期目标是确定<$2AR信号传导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。通过使用基因改变的小鼠和骨髓移植实验，检验<$2AR-反向激动剂的一个重要靶点是气道上皮细胞的假设，并确定哮喘表型的哪些组分是由于肺实质细胞与造血细胞。目标2.确定的作用？2AR--arrestin-2-MAPK信号传导，使用遗传改变的小鼠和人支气管气道上皮细胞介导<$2AR的促哮喘作用，以及Aim 3。使用药理学和遗传学的“交感神经切除术”，以及骨髓移植实验，确定肾上腺素激活<$2AR的细胞来源，允许其各种促哮喘作用，并且由于<$2AR-反向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线索。这项研究可能会导致更安全，更有效的药物治疗哮喘，并改变我们对哮喘的理解在一个范式转变的水平。

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.