Determining the Role of Creatine Kinase in Asthma

哮喘在儿童中比成人更常见，大约有620万18岁以下的儿童 仅在美国就被诊断为哮喘。儿童哮喘的持续性现在已经确定与以下因素有关： 慢性肺功能缺陷会持续到成年了解儿童哮喘的自然病程 并防止其持续到成年是至关重要的任务。虽然很大一部分 的哮喘儿童在青春期开始后克服了症状，这些因素赋予了这种恢复力， 持续性哮喘仍然是未知的。目前，既没有建立预测模型， 用于儿童哮喘长期后遗症早期危险分层的生物标志物。 最近，在一项多队列研究中，我们首次报道了血清水平和全血基因 肌酸激酶（CK）的表达在儿童哮喘中降低。CK是一种酶， 肌酸和ATP到磷酸肌酸和ADP的可逆反应-在细胞能量中起着至关重要的作用 体内平衡和缓冲。此外，我们在小鼠过敏性气道模型中进行了实验研究 由常见的过敏原屋尘螨（HDM）在存在和不存在 CK-B的药理学抑制剂。我们发现，CK-B表达显著降低24小时后， HDM攻毒，但在攻毒后5天恢复，表明其在消退期间的重要性 相位最值得注意的是，我们发现CK-B被抑制的HDM攻击小鼠表现出延长的 在气道高反应性期间，对气道中粘蛋白的存在有重大影响。 虽然这些研究首次表明CK在儿童哮喘中具有潜在的保护作用，但多项研究表明， 这种联系的要素仍有待阐明。这一建议涉及我们的总体假设， 哮喘肺环境中的因子导致CK亚型的下调，这反过来又导致 延长和恶化的哮喘表型。我们将研究关于CK亚型的3个感兴趣的领域 和哮喘，这将引导我们沿着进一步的机制理解的道路：1）CK的表达， 特定的呼吸道上皮细胞群以及对循环和肺中CK水平的影响 哮喘，2）哮喘肺环境中可能调节CK表达的特定因子的影响 以及3）在生命早期的慢性低CK是否影响小鼠成年发作哮喘的严重性。

Asthma is more common in children than adults, with approximately 6.2 million children under age 18 diagnosed with asthma in the US alone. Persistence of childhood asthma has been now conclusively linked to chronic lung function deficits that track into adult life. Understanding the natural course of childhood asthma and preventing its persistence into adult life are tasks of paramount importance. While a significant proportion of children with asthma overcome symptoms after the onset of puberty, the factors that confer this resilience to persistent asthma remain largely unknown. At present, there are neither established prediction models nor available biomarkers for early risk stratification of long-term sequelae of childhood asthma. Recently, in a multi-cohort study we reported for the first time that serum levels and whole blood gene expression of creatine kinase (CK) are decreased in childhood asthma. CK is an enzyme that – by catalyzing the reversible reaction of creatine and ATP to phosphocreatine and ADP – plays a vital role in cellular energy homeostasis and buffering. Further, we conducted experimental studies in a mouse model of allergic airway disease induced by the common allergen, house dust mite (HDM) in the presence and absence of a pharmacological inhibitor of CK-B. We discovered that CK-B expression significantly decreased 24 hrs after HDM challenge, yet recovered by 5 days post challenge, suggesting its importance during the resolution phase. Most notably, we found that HDM challenged mice in which CK-B was inhibited displayed a prolonged period of airway hyperresponsiveness and had a major impact on the presence of mucin in the airways. While these studies indicate for the first time a potential protective role of CK in childhood asthma, multiple elements of this association remain to be elucidated. This proposal addresses our overall hypothesis that factors in the asthmatic lung milieu lead to the down-regulation of CK isoforms, which in turn results in prolonged and worse asthma phenotypes. We will investigate 3 areas of interest regarding the CK isoforms and asthma that will lead us down the path of further mechanistic understanding: 1) expression of CK in specific respiratory epithelial cell populations and the impact on CK levels in circulation and in the lung during asthma, 2) the impact of specific factors in an asthmatic lung environment that may regulate CK expression and 3) if chronically low CK in early life impacts the severity of adult-onset asthma in mice.