This SCOR has its ultimate goal the cure of cystic fibrosis (CF). The studies proposed are based on the premise that understanding the origin and control of the inflammatory response in the CF lung is critical for CF therapeutics at many stages of the disease. It is our hypothesis that inflammation occurs early in the course of the CF lung disease, and must be controlled in order for other treatments to achieve maximum effectiveness. Six projects revolved around this central theme. In project 1 (P. Davis, project leader) CF mice and cell lines expressing the CF phenotype are used to explore the relationship between the CF phenotype and the inflammatory response to the most common infecting organism in CF- Pseudomonas aeruginosa. Dr. Prince's project 2 will investigate the activation by calcium of NF-kappaB, which is a central molecule in the inflammatory response. This transcription factor is activated by pseudomonas and regulates many of the inflammatory responses observed in CF, and appears to be activated in the basal state in some patients with CF. How calcium regulates NF-kappaB and how it participates in the pathogenesis of the CF lung disease is the focus of her project. Dr. Drumm's project 3 investigates potential modifier genes for CF that he has identified in mice and will identify in man, and will study not only how they affect salt transport but also how they affect the ability of the animal to respond to an infectious stimulus. Dr. Berger's project 4 investigates the role of the anti-inflammatory cytokine IL-10 in the pathogenesis of the CF inflammatory lung disease, and evaluates IL-10 as a possible therapeutic intervention. In collaboration with Dr. Konstan, he will investigate the inflammatory response early in life in CF infants and young children, as well as using animal models to determine the nature and pathophysiologic importance of this cytokine. Dr. Ferkol's project 5 will capitalize on what we have learned about the epithelial cell as a modulator and regulator of the inflammatory response and will test novel therapeutic approaches to the protection of the surface of the epithelial cells. Dr. Tosi's project 6 will investigate the relationship between the infection and inflammation in the CF lung and the effectiveness and toxicity of adenoviral mediated gene therapy. These projects will be supported by an Administrative Core and an Animal Core, directed by Dr. Richard Woychik, and will draw on other cores and investigators from the Cystic Fibrosis Research Center at Case Western Reserve University.
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