The overall goals of the SCOR are 1) to relate cystic fibrosis transmembrane regulator (CFTR) function(s) to the pathogenesis of CF lung disease, and 2) to design efficient and safe therapies for CF lung disease. The SCOR consists of four Projects and four Cores that utilize molecular biologic and physiologic techniques, and a recently generated CF """"""""knock-out"""""""" [CFTR (-/-)] mouse, to address these goals. Project IA (CFTR: Structure, Function, and Disease Pathogenesis, E. Price, P.I.) will characterize the topography of CFTR. Dr. Price combines heterologous expression systems for CFTR, epitope """"""""flagging"""""""" of CFTR domains, and the capability to generate novel high affinity monoclonal antibodies using purified CFTR and the CFTR(-/-) mouse. These studies are complemented by studies of Dr. Stutts (Mutational Analysis of CFTR Function, Project 1B) which will investigate structure/function relationships of mutated CFTRs expressed in heterologous and murine airway systems. Dr. Price (Project IA), assisted by Drs. Koller, Grubb, and Knowles, will close the loop with respect to CFTR function- pathogenesis by testing the effects of specific CFTR mutations in transgenic mice, using the CFTR(-/-) mouse as the background. Projects II and III focus on therapies of CF lung disease. Dr. Olsen (Project II, Retrovirus Mediated Gene Transfer into Airway Epithelia) will 1) identify mechanisms for increasing efficiency of retroviral entry into airway epithelial cells; 2) develop strategies to maintain gene expression in transduced airway epithelia; and 3) develop techniques for increasing airway epithelial cell proliferation in situ and """"""""depot"""""""" devices for retroviral delivery. Project III, (Therapy for CF Lung Disease, R. Boucher, P.I.) investigates cell biologic questions relevant to CF gene transfer in man. Questions to be investigated include defining: the cell types in the airway that express CFTR; the epithelial cell proliferation rates in normal and CF airways; and, the functional consequences of CFTR over-expression. A major series of studies will utilize the CFTR(-/-) mouse for developing therapies. Pharmacologic and gene transfer therapies, both transient and integrative, will be tested early and late in the course of CF lung disease. The SCOR is supported by four cores. The Administrative and Biostatistics Core (Core A, R. Boucher, P.I.) will perform administrative and data handling/analyses functions. The Tissue Culture Research Core (Core B, J. Yankaskas, P.I.) provides cellular material for investigators. The Mouse Core (Core C, B. Koller, P.I.) supplies CFTR(-/-) mice to investigators and houses transgenic mice expressing foreign CFTR cDNAs. The Morphology/Morphometry Core (Core D, M. Leigh, P.I.) will provide morphometric analyses of transgenic mice and CFTR(-/-) mice utilized in therapeutic protocols. The combination of in vitro and whole animal studies should yield important data to address major questions about CF pathogenesis and safe and efficient ways of treating CF lung disease.
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