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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Mckeon, Catherine T
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Zhang, Zhe; Reenstra, William; Weiner, Daniel J et al. (2007) The p38 mitogen-activated protein kinase signaling pathway is coupled to Toll-like receptor 5 to mediate gene regulation in response to Pseudomonas aeruginosa infection in human airway epithelial cells. Infect Immun 75:5985-92
Kobinger, Gary P; Limberis, Maria P; Somanathan, Suri et al. (2007) Human immunodeficiency viral vector pseudotyped with the spike envelope of severe acute respiratory syndrome coronavirus transduces human airway epithelial cells and dendritic cells. Hum Gene Ther 18:413-22
Bell, Peter; Vandenberghe, Luk H; Wu, Di et al. (2007) A comparative analysis of novel fluorescent proteins as reporters for gene transfer studies. J Histochem Cytochem 55:931-9
Zhang, Zhe; Louboutin, Jean-Pierre; Weiner, Daniel J et al. (2005) Human airway epithelial cells sense Pseudomonas aeruginosa infection via recognition of flagellin by Toll-like receptor 5. Infect Immun 73:7151-60
Bals, R; Wilson, J M (2003) Cathelicidins--a family of multifunctional antimicrobial peptides. Cell Mol Life Sci 60:711-20
Medina, Maria Fe; Kobinger, Gary P; Rux, John et al. (2003) Lentiviral vectors pseudotyped with minimal filovirus envelopes increased gene transfer in murine lung. Mol Ther 8:777-89
Wang, Xiaorong; Moser, Christian; Louboutin, Jean-Pierre et al. (2002) Toll-like receptor 4 mediates innate immune responses to Haemophilus influenzae infection in mouse lung. J Immunol 168:810-5
Moser, Christian; Weiner, Daniel J; Lysenko, Elena et al. (2002) beta-Defensin 1 contributes to pulmonary innate immunity in mice. Infect Immun 70:3068-72
Croyle, Maria A; Chirmule, Narendra; Zhang, Yi et al. (2002) PEGylation of E1-deleted adenovirus vectors allows significant gene expression on readministration to liver. Hum Gene Ther 13:1887-900
Bals, R; Weiner, D J; Meegalla, R L et al. (2001) Salt-independent abnormality of antimicrobial activity in cystic fibrosis airway surface fluid. Am J Respir Cell Mol Biol 25:21-5

Showing the most recent 10 out of 22 publications