Determining the Role of Creatine Kinase in Asthma

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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.