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，在美国已达到流行病的比例。 哮喘的发病机制涉及气道上皮细胞， 由于维持正常支气管直径的机制被破坏而收缩的肌肉细胞。 这后一方面的疾病是至关重要的，因为发病率和死亡率在哮喘干 因为支气管收缩导致气流受限为了设计更有效的治疗方法， 为了消除这种疾病的严重表现，我们需要确定所有系统性监管机构，这是我们的长期目标。在 特别是，我们已经收集到的证据表明，骨通过激素骨钙素有利于支气管扩张。 骨钙素是一种新发现的激素，它与一种特异性受体Gprc 6a结合后发出信号。 值得注意的是，以最高水平表达Gprc 6a的器官是肺。这促使我们研究 骨钙素是否在体内肺中发挥任何功能，使用我们已经产生的小鼠模型。另一 这样做的一个重要原因是骨钙素的循环水平在运动期间增加，当 需要支气管扩张来增加通气。我们观察到的是骨钙素-/-（OCN-/-）和 Gprc 6a-/-小鼠在基线时具有增加的气道阻力（Rn），并且在基线时具有增加的气道高反应性（AHR）。 乙酰甲胆碱是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 任何气道炎症的迹象相反，在骨钙素中携带功能获得突变的小鼠， 信号转导（Esp-/-）在基线时具有降低的Rn并且没有AHR。因此，这些结果分离了两个基数 哮喘的内分泌调节的重要性，并进一步强调支气管哮喘的内分泌调节的重要性。 直径.将骨钙素直接注入Ocn-/-小鼠的大脑并不能纠正它们的支气管收缩 表型，而其全身给药，表明骨钙素的作用，而不是外周 以控制气道直径。这些和其他初步数据在本报告的正文中提出， 应用表明，骨有利于支气管扩张通过激素骨钙素后，它结合到其 同源受体Gprc 6a在细胞类型，我们打算确定。我们提供的证据表明， 在没有骨钙素信号传导的情况下，肺中的副交感神经信号传导增加。基于这些 根据其他初步数据，我们现在提出以下具体目标： ·破译介导骨钙素调节支气管扩张的细胞和分子机制 ·确定骨钙素是否可以改善各种小鼠模型的支气管收缩症状 哮喘

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