The broad, long-term objective is to identify novel targets of therapy for cystic fibrosis (CF). Long-term infections with mucoid Pseudomonas aeruginosa prematurely kill most patients despite aggressive treatments. Therefore, new treatments must be found. CF is caused by a genetic defect in CFTR, which is a protein expressed in epithelial cells of the lung but also in inflammatory cells. The host inflammatory response to P. aeruginosa in the CF lung is exaggerated compared to normal. The reasons are unclear; understanding this inflammatory response might suggest new treatment options. Since inflammation is a highly complex process that is not well understood even in the healthy lung and there are no adequate controls in humans, mouse models of cystic fibrosis must be used. The goal of this study is to evaluate lung inflammation in response to mucoid P. aeruginosa in mouse models that express CFTR in some cells, but not in others.
Aim 1 will test whether CFTR defects in lung epithelial cells or cells derived from the bone marrow (inflammatory cells) are responsible for the exaggerated CF lung inflammation using bone marrow transplant techniques. Using flow cytometry and immunohistochemistry techniques, Aim 2 will determine whether bone marrow cells can also form into lung epithelial cells with or without P. aeruginosa lung infection.
Aim 3 will test whether CFTR defects in one inflammatory cell type (lymphocytes) are responsible for the lung host response using bone marrow transplant and adoptive transfer techniques. If cells other than lung epithelial cells are responsible for mediating this exaggerated lung inflammation, then correcting the CFTR defect in these cells becomes very important. These studies will direct future studies to more fully understand the pathophysiology of CF so novel treatments can be evaluated for use in CF patients. ? ?