Service Communautaire d'Information sur la Recherche et le Développement - CORDIS

Generation of inbred F508 del CFTR mutant mice in 4 different genetic backgrounds

A mouse breeding programme was started to obtain congenic F508del-CFTR mice in different genetic backgrounds (FVB; C57BL/6; 129/Sv; BALB/C). Attempts to include DBA as the fifth background were stopped because of the poor breeding performance of the Cftr+/- heterozygotes. The FVB and C57BL/6 strains reached their congenic state (13th backcross) in 2003, whereas congenic 129/Sv and BALB/C strains will become available in November 2004 and March 2005, respectively.

Both the FVB and C57BL/6 strains were analyzed for possible phenotypic differences with respect to
- The level of F508del-Cftr processing in intestinal and airway epithelium, using a combination of immunological and functional assays (Western blots, immunocytochemistry, ion transport in mini-Using chambers);

- The occurrence of distal intestinal obstruction syndrome (DIOS) in response to a shift in diet from Hope farms SRM-A to SDS-RM3 (obstruction, perforation and necrosis of the terminal ileum followed by death within 3-4 days after the diet shift);

- The occurrence of early symptoms of CF lung disease (goblet cell hyperplasia, interstitial collagen deposits, hypercellularity of the bronchioli, increase of inflammatory markers).

Whereas the percentage of F508del-Cftr protein escaping from the processing defect and the residual, Cftr-mediated transepithelial chloride secretion in intestinal and nasal mucosa did not differ significantly between both mouse strains, there was a remarkable strain difference in their sensitivity towards intestinal and lung disease: 100% of the homozygous F508del CF FVB mice, but 0% of the C57BL/6 mice died within 4 days after shifting to the SDS-RM3 diet, whereas all homozygous F508del CF C57BL/6 mice, but none of the FVB mice (kept on Hope Farms diet), showed clear symptoms of "spontaneous" CF lung disease.

Awaiting the mapping of the genetic loci determining these strain differences in diet tolerance and susceptibility to CF lung disease, the congenic F508del CF mouse models created in this programme can already be used advantageously to test the efficacy of novel F508del Cftr rescue therapies (both genetic and pharmacologic) in ameliorating CF intestinal disease (FVB strain) and lung disease (C57BL/6 strain), respectively.

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