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Grant

Determining the Role of Creatine Kinase in Asthma

Sponsored by National Institute of Allergy and Infectious Disease

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$230.3K Funding
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Abstract

Asthma is more common in children than adults with approximately 6.2 million children under age 18diagnosed with asthma in the US alone. Persistence of childhood asthma has been now conclusively linked tochronic lung function deficits that track into adult life. Understanding the natural course of childhood asthmaand preventing its persistence into adult life are tasks of paramount importance. While a significant proportionof children with asthma overcome symptoms after the onset of puberty the factors that confer this resilience topersistent asthma remain largely unknown. At present there are neither established prediction models noravailable 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 geneexpression of creatine kinase (CK) are decreased in childhood asthma. CK is an enzyme that by catalyzingthe reversible reaction of creatine and ATP to phosphocreatine and ADP plays a vital role in cellular energyhomeostasis and buffering. Further we conducted experimental studies in a mouse model of allergic airwaydisease induced by the common allergen house dust mite (HDM) in the presence and absence of apharmacological inhibitor of CK-B. We discovered that CK-B expression significantly decreased 24 hrs afterHDM challenge yet recovered by 5 days post challenge suggesting its importance during the resolutionphase. Most notably we found that HDM challenged mice in which CK-B was inhibited displayed a prolongedperiod 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 multipleelements of this association remain to be elucidated. This proposal addresses our overall hypothesis thatfactors in the asthmatic lung milieu lead to the down-regulation of CK isoforms which in turn results inprolonged and worse asthma phenotypes. We will investigate 3 areas of interest regarding the CK isoformsand asthma that will lead us down the path of further mechanistic understanding: 1) expression of CK inspecific respiratory epithelial cell populations and the impact on CK levels in circulation and in the lung duringasthma 2) the impact of specific factors in an asthmatic lung environment that may regulate CK expressionand 3) if chronically low CK in early life impacts the severity of adult-onset asthma in mice.

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