Cystic Fibrosis (CF) is an autosomal recessive disorder caused by defects in the CF transmembrane conductance regulator (CFTR) gene. The CFTR gene encodes a protein that functions as a cAMP-activated chloride channel and a regulator of other chloride channels. Patients with CF are predisposed to chronic endobronchial infections with organisms such as Pseudomonas aeruginosa and exhibit an exaggerated inflammatory response to these pathogens. This response is characterized by excessive NFkB activation with the subsequent release of potent proinflammatory cytokines. These cytokines promote a massive influx of neutrophils in the conducting airways. Once in an airway lumen, neutrophils release a variety of substances that either directly or indirectly damage the lungs. These substances include neutrophil elastase (NE), which can cause bronchiectasis, airway obstruction, and impaired clearance of infected secretions. In time, it Is lung destruction by neutrophil by-products and airway obstruction rather than infection that causes respiratory failure in a majority of CF patients. The objective of this proposed research project is to determine whether CF lung disease can be ameliorated by the controlled expression of anti-inflammatory molecules from rAAV vectors. In addition to pursuing the outlined research project, my immediate goals for the future as include obtaining further training in the methodology of translating experimental findings in biomedical research into clinically useful applications. A K30 program designed to educate new faculty in the principals of translational research is available at the University of Florida. I will be enrolled in this program, which includes didactic courses in statistics, clinical study design and ethics. This program should prove invaluable in instructing me how to design, implement and interpret clinical studies aimed at examining the role of anti-inflammatory gene therapy for lung disease. I will devote 80 percent effort over the 5-year award period to the accomplishment of the above goals. The experience and skills acquired during this time period will provide me future opportunities to develop other patient-oriented research projects in my area of interest and to obtain independent funding for these projects. In the long term, I look forward to continuing an academic career focused on translational research in the area of anti- inflammatory gene therapy for lung disease.
| Buff, S M; Yu, H; McCall, J N et al. (2010) IL-10 delivery by AAV5 vector attenuates inflammation in mice with Pseudomonas pneumonia. Gene Ther 17:567-76 |
| Virella-Lowell, Isabel; Zusman, Benjamin; Foust, Kevin et al. (2005) Enhancing rAAV vector expression in the lung. J Gene Med 7:842-50 |
| Virella-Lowell, Isabel; Herlihy, John-David; Liu, Barry et al. (2004) Effects of CFTR, interleukin-10, and Pseudomonas aeruginosa on gene expression profiles in a CF bronchial epithelial cell Line. Mol Ther 10:562-73 |
| Sirninger, Jeffrey; Muller, Christian; Braag, Sofia et al. (2004) Functional characterization of a recombinant adeno-associated virus 5-pseudotyped cystic fibrosis transmembrane conductance regulator vector. Hum Gene Ther 15:832-41 |
