Grant: Operating Grant

Cystic fibrosis (CF) is the most common, fatal genetic disease affecting young Canadians. CF is an autosomal recessive condition caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. It is estimated that one in every 3,600 children born in Canada has CF and approximately one in every 25 Canadians carries a defective version of the gene responsible for CF. Unfortunately, twenty years after identification of the cftr gene, controversies still surround the pathogenesis of airway disease. This gap in our understanding of CF airways disease makes the development of new and effective treatments more difficult. Here we propose to test the hypothesis that CF pathogenesis is the failure to secrete mucus and fluid containing antimicrobial compounds in response to inhaled pathogens. We propose that in normal airways the inhalation of bacteria triggers CFTR-mediated mucus and fluid secretion required to trap and kill bacteria. This secretion is absent in CF airways thus facilitating infection and chronic inflammation. For this study we will use a genetically modified swine that display airway disease that resembles that of CF humans to study the response to inhaled bacteria. We have developed a synchrotron-based imaging method that allow us to measure mucus and fluid in living swine and to quantify the amount of secretion in response to inhaled bacteria. There is no other technique to measure mucus secretion in living animals and, in addition to more traditional methods, will allow us to study CF airway disease pathogenesis and progression. This grant would be best evaluated in the "Respiratory System" review committee. This committee reviewed the previous version of this grant last year and the topics covered in the grant match the expertise of the committee members.