Creatine Kinase in the Natural History of Asthma

PROJECT SUMMARY/ABSTRACT In a recent multi-cohort discovery 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, in preliminary studies on a subset of participants with asthma from the TCRS birth cohort we observed that, among 6-years old children with asthma, those with high circulating levels of CK had a striking 80% reduction in their risk of persistent disease into adult life. These results, together with those from experimental studies that we have completed, indicate that CK may play a protective role in asthma. However, multiple elements of this association remain to be elucidated and this R21 application will use observational data from multiple cohorts to address two critical questions. First, although our preliminary data indicate that, among school-age children with asthma, high levels of circulating CK may confer protection against persistence of disease, these studies are based on a single cohort, a single CK measurement, and a small number of asthmatics and require validation in a larger consortium. Second, it remains unknown whether, in addition to circulation, CK deficits are also present in the airways of individuals with asthma, a question of critical importance because of the role of CK in sustaining the ciliary beat and, in turn, enhancing the first defensive mechanism of the lungs. This R21 application seeks to overcome these knowledge gaps through the following specific aims: Specific aim 1: To determine whether circulating levels of CK predict persistence of childhood asthma into adult life in multiple population-based cohorts. Specific aim 2: To characterize and compare CK gene expression in airway epithelial cells from individuals with and without asthma.