Paediatric disordersHow useful are cystic fibrosis mouse models?
Section editor:
Gabriel Haddad – Pediatrics Department, University of California, San Diego, CA, USA
Introduction
Cystic fibrosis is one of the most common multi-system life shortening genetic disorders in the Caucasian population affecting one in 2500–3500 live births. The disease affects the respiratory tract, digestive tract, eccrine sweat glands and reproductive tracts [1]. CF is a life shortening with an average life expectancy of 35 years. The genetic basis for the disease was identified in 1989 when the gene that encodes for the cystic fibrosis transmembrane conductance regulator [CFTR] was identified by Collins, Riordan and Tsui [2]. Soon after the identification of the gene research began to develop animal models that would help elucidate the natural history of the basic pathophysiology of this deadly disease. Investigators also hoped that these models would provide a viable model for drug development and gene therapy development. Presently a variety of mouse models are available and they have provided significant insight into many aspects of the disease process; however, the mouse models do not always mimic the human disease. For instance the mice do not develop spontaneous Pseudomonas bronchitis and suppurative lung disease that is a hallmark of the human disease process. This has led some investigators to abandon these models. In this review we will summarize the available models and highlight the characteristics that have made them important tools for advancing our understanding of the pathophysiology that leads to end organ damage and as in vivo models for drug development.
Section snippets
Murine models of CF
Murine models of CF were developed shortly after the identification of the CFTR gene. The first models were generated by using a gene targeting strategy in which the endogenous CFTR gene is disrupted in embryonic stem cells. This strategy results in a null allele and no detectable mRNA nor functional protein and was used to generate several models (Table 1). Alternatively, several groups used an insertional method to disrupt the endogenous CFTR gene. These models produce low levels of CFTR mRNA
The clinical phenotypes of CF mouse models
The clinical manifestations of cystic fibrosis are diverse and span many organ systems. Common respiratory manifestations include nasal polyps, sinus disease, chronic obstructive lung disease which results in respiratory failure [7]. The gastrointestinal manifestations include focal biliary cirrhosis, distal ileal obstruction, exocrine pancreatic insufficiency, meconium ileus and rectal prolapse. Women demonstrate decreased fertility and the majority of males are infertile owing to bilateral
Summary
The murine models display many manifestations observed in the human disease including alterations in respiratory and intestinal epithelial electrophysiology, robust airway inflammation, intestinal obstruction, pancreatic dysfunction, hepatobiliary disease and bone disease. However, many of these manifestations are much milder in the CF mouse when compared with humans. Moreover, the spontaneous chronic pseudomonas bronchitis that is a hallmark finding in humans is not observed in any of the
Usefulness of the models and future directions
Because there are species differences in the respiratory tract between mice and humans the models might allow us to determine how these differences impact the disease state. For instance unlike humans, the mouse does not have submucosal glands in the lower respiratory tract and it has an alternative chloride channel in the lower tract. Both of these differences might provide the mouse with protection from chronic colonization with the common bacteria usually observed in CF airways.
In addition,
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Cited by (16)
Animal and Cell Culture Models for Cystic Fibrosis: Which Model Is Right for Your Application?
2021, American Journal of PathologyCitation Excerpt :A large number of CF mouse strains have since been documented and characterized in the literature. These mice can be broadly classified into three categories: i) Cftr null or knockout (KO) models,7,26 ii) strains with human CF-causing mutations introduced into the mouse Cftr gene (eg, Phe508del, Gly551Asp, and G542X),38 and iii) transgenic models [eg, gut-corrected models, mice expressing human CFTR, and β-epithelial sodium channel (β-ENaC) mice].9,27,39 Phenotype severity varies among CF mouse strains as a result of the method used to disrupt the Cftr gene, the type of mutation introduced, and the levels of Cftr mRNA produced.8
Modification of the salivary secretion assay in F508del mice - The murine equivalent of the human sweat test
2013, Journal of Cystic FibrosisCitation Excerpt :Best and Quinton developed a salivary secretion assay in CFTR deficient mice to study CFTR-dependent saliva secretion [8], which was later partially extended to F508del transgenic mice [9,10]. Nevertheless, there is only limited information on the effects of potential new CF-treatment options available [9,11] and questions are raised about the predictive value of these in vivo assays in CF mice [12,13]. This is partly due to the lack of consistent and systematic in vivo data in the CF mouse models, which are rather difficult to obtain since different murine backgrounds, different sexes and different transgenic animals are used.
Preface
2013, Translational NeuroimagingComparative processing and function of human and ferret cystic fibrosis transmembrane conductance regulator
2012, Journal of Biological ChemistryCitation Excerpt :Essential to development of effective therapies for CF are animal models that recapitulate the human disease phenotype. Although mouse models of CF have been very useful, they lack development of spontaneous lung disease with the phenotypic characteristics of humans with CF (3–5). To this end, ferret and pig CF models have been generated, and both develop CF-like lung disease (6, 7).
Alterations of skeletal muscle bioenergetics in a mouse with F508del mutation leading to a cystic fibrosis-like condition
2019, American Journal of Physiology - Endocrinology and Metabolism