and specific aims): Cystic fibrosis (CF) is an autosomal recessive disease associated with life limiting pathology in the lung characterized by recurrent bacterial infections, obstructive lung disease, bronchiectasis, and respiratory failure. The overall goal of this renewal application is to build on experience with the xenograft model to evaluate the role of epithelial defensin activity in CF and the ability to reverse the defect by gene transfer. The following hypotheses will be evaluated: 1) abnormalities in CF ASF leads to defects in bacterial killing which contribute to the pathogenesis of chronic respiratory infection, 2) airway epithelial cells contribute to normal host defense by secreting into ASF antimicrobial peptides called b-defensins of which human b-defensin type I (HBD-I) is a prototype, and 3) gene transfer can effectively correct the primary defect in bacterial killing.
The specific aims : 1) characterize the antimicrobial activity in the ASF of non CF intrapulmonary epithelia that is defective in CF and study its correction by in vivo gene transfer; 2) evaluate the role of candidate epithelial b-defensin genes in the host's defense to pulmonary bacterial infection and whether its function is compromised in CF; and 3) genes encoding other defensins expressed in airway epithelia will be isolated and characterized as described in Specific Aim 2.
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