MOLECULAR BASIS OF THE CYSTIC FIBROSIS PHENOTYPE

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The goal of this SCOR application is to understand the clinical, biological and biochemical consequences of mutations in CFTR, the gene defective in cystic fibrosis (CF). The program brings together a group of basic scientists and clinician researchers with a broad range of expertise to the common task of analyzing the CF disease from different angles, through studying the CFTR molecular defects in patients, generating, mouse models, mapping of modifier genes, and using cell culture and in vitro systems for the protein. We combine our strengths in the area of CF patient documentation, human and mouse genetics, biochemistry and cell biology. The SCOR is organized into 4 Research Projects (RP), 3 Pilot Projects (PP) and 3 Core Units, grouped into 3 research areas, namely, clinical and genetic studies of patients, mouse models of identification of CF modifier genes, and direct characterization of CFTR. In the first area, RP1 will establish a comprehensive understanding of the spectrum of CF disease phenotype caused by or associated with the primary and secondary genetic determinants of the disease. In the second, RP2 will study the role of ClC-2 chloride channels in mediating epithelial chloride secretion in a mouse model and RP3 will dissect the physiologic and genetic aspects of lung disease in CF mice of a specific genetic background. In addition, a pilot project, PP3, is included to characterize the liver disease recently observed in one of the congenic CF mouse strains. These studies will discover new pathways through which alternative methods may be devised to treat CF. In the third area, RP4 will pursue a detailed analysis at the molecular, cellular and functional levels to establish the consequences of the missense mutations that occur in the first nucleotide binding domain (NBD1) of CFTR and mutations causing carboxyl terminal truncations will be used as probes for these studies. This will be complemented by the two pilot projects: PP1 which will explore a new fluorescence transfer technique for the study of transmembrane segment interactions and PP2 which will examine if purified CFTR an mediate energy-dependent transport of large organic anions such as glutamate and glutathione in a reconstituted system. In addition to the Administration Core, the Patient/Biostatistics Core, and the Mouse Core will serve to support the hove projects. The results from Score should yield novel insights into the molecular mechanisms of CF pathology and should lead to new improved therapeutic approaches.