Cystic fibrosis (CF) is a common, lethal, autosomal recessive disorder caused by mutations in the CFTR gene, with the most common mutation (ΔF508) occurring on ∼70% of CF chromosomes. Dysfunction of the CFTR protein, which acts as an apically localized epithelial chloride ion channel, results in the classical manifestations of CF: salty sweat, pancreatic insufficiency, intestinal obstruction, male infertility, and severe pulmonary disease, with characteristic abnormalities in electrolyte transport. The most serious consequence is progressive and ultimately fatal inflammatory lung disease characterized by chronic microbial colonization and repeated acute exacerbations of pulmonary infection, with a distinctive spectrum of pathogens. These clinical manifestations show considerable variation between individuals because of an as yet incompletely understood combination of environmental factors, independently segregating disease-modifying genes, and differences between specific CFTR mutations. The development of mouse models for cystic fibrosis has provided the opportunity to dissect disease pathogenesis, correlate genotype and phenotype, study disease-modifying genes and develop novel therapeutics.
This review discusses the successes and the challenges encountered in characterizing and optimizing these models. CF mouse models demonstrate wide evidence of intestinal disease, but they exhibit large variation in survival, anatomically confined CF ion transport defect, and general absence of CF-like lung disease. The breeding of Cftr-null mice onto different mouse genetic backgrounds can also alter disease severity, suggesting that other genetic loci may modify the severity of CFTR mutations ( Rozmahel et al., 1996).
Although they look very different to us, species as diverse as yeast, flies, worms, zebra fish, dogs and mice share a lot of genes and molecular pathways with humans. Therefore, by studying these so-called 'model organisms', researchers can learn a lot about human biology and human diseases and health problems. Indeed, 99% of mouse genes have an equivalent in humans, making mice ideal for studying the function of human genes in health as well as diseases such as cancer, cardiovascular diseases and diabetes. These multifactorial diseases are in part due to mutations in our genes.
Although there are species (such as dogs, pigs and non-human primates) that are even more closely related to us than mice, working with these large animals is extremely expensive and is fraught with ethical concerns. With their small size and short generation times, breeding and keeping mice is comparatively simple and inexpensive. In addition, because they have been widely used in research for decades, researchers have built up a detailed understanding of mouse biology and genetics and developed large numbers of tools and techniques to study them. These powerful genetics tools are not yet available for larger mammals.
Generation of delta F508 MICE knockout mice....