Hormonal regulation of airway diameter by bone and its implication to asthma

摘要 哮喘是一种异质性肺部疾病，在美国已经达到流行的程度。 哮喘的发病机制涉及呼吸道上皮细胞对胰岛素的反应和气道畅通 由于维持正常支气管径的机制被破坏而收缩的肌肉细胞。 这种疾病的后一个方面是至关重要的，因为哮喘的发病率和死亡率 由于支气管收缩而造成的气流受限。为了给大多数人设计更有效的治疗方法 对于这种疾病的严重表现，我们需要确定所有的系统性调节因素，这是我们的长期目标。在……里面 特别是，我们收集的证据表明，通过激素骨钙素的骨骼有利于支气管扩张。 骨钙素是一种新近被描述的激素，它在与特定的受体Gprc6a结合后发出信号。 值得注意的是，表达Gprc6a水平最高的器官是肺。这促使我们研究 在我们建立的小鼠模型中，骨钙素在活体肺中是否发挥任何功能。另一个 这样做的重要原因是循环中的骨钙素水平在运动过程中增加，当 需要进行支气管扩张以增加通气量。我们观察到的是骨钙素-/-(OCN-/-)和 Gprc6a-/-小鼠在基线时的气道阻力(Rn)和气道高反应性(AHR)增加 乙酰甲胆碱，哮喘的标志。值得注意的是，这种疾病的这两个特征是在缺乏 任何呼吸道炎症的证据。相反，携带骨钙素功能突变的小鼠 信号(ESP-/-)在基线时降低了Rn，没有AHR。因此，这些结果分离了两个基数 哮喘的表现，并进一步强调支气管内分泌调节的重要性 直径。骨钙素直接注入OCN-/-小鼠脑内并不能纠正它们的支气管收缩 表型，而它的全身给药表明骨钙素是外周作用的，而不是 集中控制呼吸道直径。这些数据以及本文件正文中提供的其他初步数据 应用提示，骨骼在与其结合后，通过激素骨钙素促进支气管扩张 我们打算鉴定的一种细胞类型中的同源受体Gprc6a。根据细胞类型，我们提供的证据表明 在缺乏骨钙素信号的情况下，肺中的副交感神经信号增加。基于这些 关于其他初步数据，我们现在提出以下具体目标： ·破译骨钙素调节支气管扩张的细胞和分子机制 ·确定骨钙素是否能改善不同小鼠模型的支气管收缩症状 哮喘的症状

Abstract Asthma is a heterogeneous lung disease that has reached epidemic proportions in the U.S.A. The pathogenesis of asthma involves airway epithelial cells that respond to insulting agents and airway smooth muscle cells that constrict because of the disruption of mechanisms that maintain normal bronchial diameter. This latter aspect of the disease is critically important because the morbidity and mortality in asthma stems from airflow limitation due to bronchoconstriction. In order to design more effective therapies for the most crippling manifestation of the disease, we need to identity all systemic regulators, which is our long-term goal. In particular, we have gathered evidence that bone via the hormone osteocalcin favors bronchodilation. Osteocalcin is a newly described hormone that signals following its binding to a specific receptor, Gprc6a. Remarkably, the organ that expresses Gprc6a at the highest level is the lung. This prompted us to study whether osteocalcin exerts any function in the lungs in vivo using mouse models we had generated. Another important reason to do so is that circulating levels of osteocalcin increase during exercise, when bronchodilation is needed to increase ventilation. What we observed is that Osteocalcin-/- (Ocn-/-) and Gprc6a-/- mice have increased airway resistance (Rn) at baseline and airway hyper-responsiveness (AHR) to methacholine, a hallmark of asthma. Remarkably, these two features of the disease develop in the absence of any evidence of airway inflammation. Conversely, mice harboring a gain of function mutation in osteocalcin signaling (Esp-/-) have decreased Rn at baseline and no AHR. Thus, these results dissociate two cardinal manifestations of asthma and further underscore the importance of the endocrine regulation of bronchial diameter. That osteocalcin infusion directly into the brain of Ocn-/- mice did not correct their bronchoconstriction phenotype whereas its systemic administration did, suggest that osteocalcin acts peripherally rather than centrally to control airway diameter. These and other preliminary data presented in the body of this application suggest that bone favors bronchodilation through the hormone osteocalcin after it binds to its cognate receptor Gprc6a in a cell type we intend to identify. Suggesting the cell type, we provide evidence that in absence of osteocalcin signaling there is increased parasympathetic signaling in the lungs. Based on these and on other preliminary data we now propose the following specific aims: · To decipher the cellular and molecular mechanism that mediates osteocalcin regulation of bronchodilation · To determine whether osteocalcin can improve symptoms of bronchoconstriction in various mouse models of asthma