Cystic fibrosis (CF) and alpha1-antitrypsin (alpha1AT) deficiency are the two most common lethal hereditary disorders in the USA and Europe. The major clinical manifestations of both are in the lung. CF results from mutations of the cystic firboris transmembrane conductance regulator (CFTR) gene, a 27 exon gene occupying 250 kb of chromosome 7. All organs with exocrine glands are affected, but the major clinical manifestations are in the lung, with impacted mucus, clinic infection, inflammation, and airway and parenchyma derangements. Studies over the past year have centered on understanding the control of expression of the CFTR gene and devising strategies to clear the lung of purulent mucus and protecting the respiratory epithelium from the chronic neutrophil dominated inflammation that characterizes the disease. alpha1AT deficiency results from mutations in the alpha1AT gene, a 7 exon gene occupying 12 kb of chromosome 14 causing a systemic deficiency of alpha1AT, the major inhibitor of destructive proteolytic enzyme, neutrophil elastase. In the context of the deficiency of alpha1AT, neutrophil elastase released by neutrophils in the lung goes uninhibited, resulting in progressive destruction of the lung and eventual emphysema. Recent studies have concentrated on the mechanisms of attraction of neutrophils, and enhanced neutrophil elastase to the lung in this disorder. For both cystic fibrosis and alpha1AT deficiency major emphasis is being placed on gene therapy (see project ZO1 HL 02536-01 PB).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Intramural Research (Z01)
Project #
1Z01HL002407-18
Application #
3843337
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
18
Fiscal Year
1992
Total Cost
Indirect Cost
Name
National Heart, Lung, and Blood Institute
Department
Type
DUNS #
City
State
Country
United States
Zip Code