Cystic fibrosis (CF) lung disease is characterized by chronic colonization/infection of the airways by a variety of bacteria, including H. influenzae, S. aureus, P. aeruginosa and other Gram negatives. For CF most patients, the lung disease begins soon after birth. Bacteria grow in areas of the lung that are normally sterile and the clinical course correlates with the acquisition of bacterial infection and its progression. While the pathogenic mechanisms linking CFTR mutations to CF lung disease continue to be a subject of research and debate, it is widely accepted that the normal host defense barriers in the lung are breached. Whatever the cause underlying this propensity for infection, it is lung specific. The result is a characteristic susceptibility to bacterial infection. These features indicate that CF impairs the innate defenses of the lung. Our laboratory is particularly interested in understanding the host defense contributions of newly discovered beta-defensins and novel proteins of the lipid transfer/lipopolysaccharide binding protein (LT/LBP) family. We hypothesize that a subset of the beta-defensin and LT/LBP genes are expressed in airway epithelia and play roles in innate host defense through their antimicrobial and/or lipid binding properties. There are two aims.
The first aim will determine which beta-defensin peptides contribute to innate immunity in the airways and characterize their host defense activities.
The second aim will investigate how members of the LT/LBP family contribute to innate immunity. We hypothesize that they exert BPI-like antimicrobial/anti-inflammatory activities in the airways. Addressing these aims will further our understanding of the role products of these two gene families play in the pulmonary innate immune system. By increasing our knowledge of the antimicrobial components of the innate immune system we may gain insights into CF lung disease pathogenesis and devise new therapeutic approaches.
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