Mouse models of cystic fibrosis

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  • 0168-9525/01/$ see front matter 2001 Elsevier Science Ltd. All rights reserved. PII: S0168-9525(01)02452-0 S29

    TRENDS in Genetics, Vol.17 No.10, October 2001 A TRENDS Guide to Mouse Models of Human Diseases | Review

    Donald J. Davidson*University of British

    Columbia, BC Research

    Institute for Child and

    Family Health, Room 381,

    950 West 28th Avenue,

    Vancouver, British Columbia,

    Canada V5Z 4H4.

    *e-mail: donald@cmdr.ubc.ca

    Mark RolfeMedical Research Council

    Human Genetics Unit,

    Western General Hospital,

    Crewe Road, Edinburgh,

    UK EH4 2XU.

    Cystic fibrosis (CF) is a common, lethal, autosomal recessivedisorder caused by mutations in the CFTR gene, with themost common mutation (F508) occurring on ~70% ofCF chromosomes. Dysfunction of the CFTR protein, whichacts as an apically localized epithelial chloride ion channel,results in the classical manifestations of CF: salty sweat,pancreatic insufficiency, intestinal obstruction, male infertil-ity, and severe pulmonary disease, with characteristic ab-normalities in electrolyte transport. The most seriousconsequence is progressive and ultimately fatal inflam-matory lung disease characterized by chronic microbialcolonization and repeated acute exacerbations of pulmonaryinfection, with a distinctive spectrum of pathogens.Theseclinical manifestations show considerable variation betweenindividuals because of an as yet incompletely understoodcombination of environmental factors, independentlysegregating disease-modifying genes, and differences between specific CFTR mutations.

    A combination of chest physiotherapy, aggressiveantibiotic therapy and pancreatic enzyme supplementationconstitutes the traditional mainstay of treatment for CF.Despite the success of these therapies, novel approachesare required, both to achieve further increases in life ex-pectancy and to improve quality of life rather than simplyto alleviate symptoms. As our understanding of the molecular and biological basis of CF becomes more com-prehensive, so the goal of successful treatments becomesmore accessible.

    Generating mouse models of cystic fibrosisThe first mouse models of CF were created within threeyears of the isolation of the human CFTR gene. To date,11 different mouse models of CF have been characterized(Table 1). These models can be categorized as those de-signed simply to disrupt Cftr expression and those thatspecifically model various human clinical mutations. Theformer can be further subdivided into those that used areplacement strategy to disrupt the Cftr gene, creating absolute nulls (with no normal CFTR production), andthose that used insertion into the target gene without lossof genomic sequence, in which the mutants retain the

    potential to produce low levels of normal Cftr mRNA byvarious mechanisms.These distinctions affect the phenotypeof the models and must be recognized in any interpretationof the phenotypes observed.

    Phenotypes of mouse models of cystic fibrosisCharacterization of the different mouse models of CF hasdemonstrated most of the same primary phenotypes,including intestinal obstruction, reduced fertility andcharacteristic intestinal and airway electrophysiology, re-producing many of the manifestations of CF in humans.Important differences have been observed, however, bothbetween different models (particularly in survival rates),and between mouse models of CF and human diseasepatterns (most clearly observed in pancreatic function andthe murine pulmonary phenotype).The phenotypic vari-ations between mouse models have been shown to relateto the specific mutation of Cftr generated, to environmentalinfluences and to independently segregating modifiergenes. Given rigorous evaluation, these differences providethe means to start dissecting the key components in dis-ease pathogenesis; however, the need to clearly define themouse model studied becomes obvious. In addition, themost robust phenotypes have provided in vivo models forthe development and optimization of novel therapeutics.

    Survival and intestinal diseaseIntestinal pathology and the resultant mortality are thehallmarks of Cftr mutation in the mouse. Considerablevariation in the specific pathology and the degree ofseverity has been reported between different models. Inmost cases, however, characterization of the mutant micehas revealed abnormal electrophysiological profiles, runt-ing and failure to thrive, goblet cell hyperplasia, mucinaccumulation, crypt dilation and intestinal obstruction(bearing similarity to meconium ileus, present in 1015%of CF patients) with resultant perforation, peritonitis anddeath. Studies characterizing the electrophysiological profilehave found broadly similar phenotypes in the differentmodels (Table 2) with a significant decrease in the baselinepotential difference (probably representing a decreased

    Mouse models of cystic fibrosisDonald J. Davidson and Mark Rolfe

    The development of mouse models for cystic fibrosis has provided the opportunity todissect disease pathogenesis, correlate genotype and phenotype, study disease-modifyinggenes and develop novel therapeutics. This review discusses the successes and thechallenges encountered in characterizing and optimizing these models.

    In association with MKMD

    http://research.bmn.com/mkmd

  • rate of unstimulated Cl secretion) and a complete absence,or a significant decrease, in cAMP-stimulated Cl secretion(indicative of the loss of CFTR function). These profilescan be used to distinguish unequivocally mutants fromtheir wild-type (wt) littermates and closely model theelectrophysiological phenotype in CF humans.

    The survival rates of the different mouse models gen-erally reflect the severity of intestinal pathology and varyfrom

  • similar to suggest the same pathophysiological processes,validating their use as models for human disease and therelevance of these findings for novel therapy development.

    Pancreatic diseasePancreatic insufficiency is a prominent manifestation ofCFTR dysfunction in humans, but has not been convinc-ingly demonstrated in most mouse models of CF.This ap-pears to be the result of low levels of expression of Cftr inthe murine pancreas and the presence of an alternativefluid secretory pathway, which is activated by increases inintracellular calcium7.This indicates that other ion channelsmight be capable of compensating for the loss of CFTRand suggests novel therapeutic approaches in humans,namely to identify and utilize such pathways.

    One study of Cftrtm1Unc/Cftrtm1Unc mice weaned on a liquiddiet to increase survival rates, demonstrated significantdifferences in pancreatic growth and specific enzyme ac-tivities8. Similar, although less severe, abnormalities in wtcontrols, however, suggested that the abnormalities werepredominantly secondary to malnutrition. A further studyusing a liquid elemental diet reported luminal dilatation

    and the accumulation of zymogen granules at the apicalpole of the ductal epithelial cells in Cftrtm1Unc/Cftrtm1Unc

    mice. This phenotype has since been used, and correctedwith oral administration of docosahexanoic acid (DHA),in a study of the role of dietary fatty acids in CF (Ref. 9).This study suggested that a primary defect in fatty acidmetabolism might play a significant role in the pathogen-esis of CF and indicated DHA as a novel therapy. However,the role of the liquid diet in this phenotype might yetprove to be significant.

    Lung diseaseLung disease represents the primary concern in CF andthe manifestation for which an animal model is likely tobe the most valuable. Although a variety of pulmonaryabnormalities have been reported, these are complex,mostly precipitated in response to exposure to patho-gens, and do not fully replicate the pathogenesis of lungdisease in CF individuals. Nevertheless, the developmentof lung phenotypes secondary to the loss of CFTR func-tion in mice provides an important in vivo system to studythe pathogenesis of CF lung disease.

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    TRENDS in Genetics, Vol.17 No.10, October 2001 A TRENDS Guide to Mouse Models of Human Diseases | Review

    Table 2. Intestinal electrophysiology in mouse models of cystic fibrosisa

    Mutation Tissue Baseline PD cAMP-mediated Ca2+-related Refs

    Cl response Cl response

    CF human GI tract or Cftrtm1Unc Jejunum 100% 47

    Caecum 100% 48Colon 100% 48

    Cftrtm1Hgu Jejunum 65% 49Caecum 65% 49

    Cftrtm1Cam Caecum 100% n.r. 41Cftrtm1Hsc Rectum n.r. 100% 3

    Ileumb n.r. 100% 3Cftrtm1Bay Ileum 80% n.r. 42Cftrtm3Bay Colon n.r. 100% 43Cftrtm2Cam Colon 100% 44Cftrtm1Kth Jejunum 100% n.r. 45CftrtmEur Ileum 66% 46

    Caecum n.r. 92% n.r 50Cftrtm1G551D Jejunum 99% n.r. 6

    Caecum 95% n.r. 6Cftrtm2Hgu Caecum c

    aComparison of the electrophysiological profiles of the intestinal epithelium in human cystic fibrosis (CF) and mousemodels of CF, on the original background strain. Increased (), decreased () or preserved () potential difference(PD) in comparison with non-CF controls. Abbreviations: GI, gastrointestinal tract; n.r., not reported. bPatch-clamped, isolated ileal crypt cells. cDickinson, P. et al., Generation of a CF mutant mouse possessing the G480C mutation. 22nd European CysticFibrosis Conference, 1319 June 1998, Berlin.

  • Electrophysiological studiesElectrophysiological analyses of nasal and tracheal airwayepithelia (Tables 4 and 5) in mouse models of CF havebeen shown to differentiate clearly between mutants andwt littermates, even in the absence of gross pathology.These studies clearly demonstrate the basic ion-channeldefect, with the nasal epithelium of mouse models of CFaccurately replicating the human profile. Analysis of thetrachea has, however, proved to be more complex, withimportant differences in both sodium- and chloride-iontransport observed between murine and human profiles.Indeed, it has been proposed that alternative chloride-ionpathways dominate over CFTR in the mouse trachea andmight alleviate the effects of CFTR dysfunction10.The extentto which these observations are replicated in the lowerairways remains unknown.

    Analyses of inbred mouse strains have revealed consid-erable variation and demonstrated that the ion transportproperties in the murine airways are regulated by indepen-dently segregating modifier genes.Thus, the consequencesof CFTR dysfunction in the trachea might vary considerablybetween different mouse models of CF.This raises the possi-bility of dissecting out the component parts of the electro-physiological response and establishing their relative contributions to disease pathogenesis.

    The ability to distinguish, unequivocally, mutant micefrom wt littermates using electrophysiological profiles has

    been crucial in the use of mouse models of CF for testingthe efficacy of novel therapies, particularly somatic genetherapy. The basis of the gene therapy strategy for CF isthe prevention of disease development by direct replace-ment of CFTR gene function, irrespective of a completeunderstanding of disease pathogenesis. Gene correctionstrategies must therefore be demonstrated to be safe andeffective so that intervention can be attempted in infants.Successful correction towards the wt pulmonary electro-physiological phenotype has provided the primary end-point for analyses in mouse models of CF, using purifiedCFTR protein11 and both adenoviral-based12 and lipo-some-based13,14 gene therapy vectors. These studies wereinstrumental in the initiation of human gene therapy trials,provided results similar to those achieved in humans, andrevealed many of the same obstacles to successful correc-tion. These issues, such as low transfection efficiency,transient expression and effect of repeat administration, arenow being addressed. Mouse models continue to prove animportant resource in this development and optimizationprocess and bridge the gap between cell-culture-basedstudies and human trials.

    Lung pathologyThe use of electrophysiological profiles has been of greatimportance in the development of novel therapies; how-ever, disease state endpoints are also vital to evaluate the

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    Review | A TRENDS Guide to Mouse Models of Human Diseases TRENDS in Genetics, Vol.17 No.10, October 2001

    Table 3. Survival in mouse models of cystic fibrosisa

    Mutation Perinatal death Survival to maturity Body weight Refs

    F508 CF human 10% MI 20% DIOS Failure to thriveCftrtm1Unc null 50% by day 7

  • pathophysiological consequences. These have proved tobe considerably more complex (Table 6).

    The first observations relating to abnormal lungpathology in mouse models of CF were made in outbredMF1/129 Cftrtm1Hgu/Cftrtm1Hgu mice. No gross lung diseasewas observed at birth, or in animals born and raised inisolator conditions15, but cytokine abnormalities wereobserved in mutant mice maintained in standard animalfacilities16.These observations and the studies that followedsuggest that an abnormal lung phenotype might notmanifest without exposure to pathogens. In response toexposure to aerosolized clinical isolates of Staphylococcus aureus and Burkholderia cepacia, Cftrtm1Hgu/Cftrtm1Hgu mice demon-strated significantly impaired airway clearance and the

    development of significantly more severe, pathogen-specific,lung pathology15.These observations in response to clini-cally relevant B. cepacia infection have recently been repeatedand elaborated upon using Cftrtm1Unc mice maintained on aliquid diet17. This recent model also demonstrates an increased influx but suboptimal activation of inflamma-tory cells in the lungs of the mutant mice. In earlier stud-ies, however, abnormal lung pathology was not observedin Cftrtm1Unc mice following exposure to S. aureus (Ref. 18).It is probable that mutation-specific effects, differences inthe mouse-strain backgrounds (particularly variations inthe role of alternative airway epithelial ion-channels) andvaried methods of bacterial exposure influence thesecontrasting observations.

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    TRENDS in Genetics, Vol.17 No.10, October 2001 A TRENDS Guide to Mouse Models of Human Diseases | Review

    Table 4. Nasal electrophysiology in mouse models of cystic fibrosisa

    Mutation Baseline PD Amiloride cAMP-mediated Ca2+-related Refs

    response Cl response Cl response

    CF human Cftrtm1Unc 100% 51Cftrtm1Hgu 70% 49Cftrtm1Cam n.r. n.r. n.r. 13Cftrtm1Hsc 100% 52Cftrtm1Eur Response to Cl gradient 46Cftrtm1Kth 100% n.r. 45Cftrtm1G551D 100% 6aComparison of the electrophysiological profiles of the nasal epithelium in human cystic fibrosis (CF) and mousemodels of CF, on the original mixed genetic background strains. Profiles are shown as increased (), decreased ()or preserved () potential difference (PD) in comparison with non-CF controls. Amiloride inhibits the epithelialsodium channel EnaC.Abbreviation: n.r., not reported.

    Table 5. Tracheal electrophysiology in mouse models of cystic fibrosisa

    Mutation Baseline PD Amiloride cAMP-mediated Ca2+-related Refs

    response Cl response Cl response

    CF human or Cftrtm1Unc 10

    Cftrtm1Hgu 60% 49Cftrtm1Cam 75% 13Cftrtm1Bay n.r. b 70% n.r. 42Cftrtm2Cam c to 60% 44Cftrtm1G551D 60% 6aComparison of the electrophysiological profiles of the tracheal epithelium in human cystic fibrosis (CF) and mousemodels of CF on the original mixed genetic background strains. Increased (), decreased () or preserved ()potential difference (PD) in comparison to non-CF controls. Amiloride inhibits the epithelial sodium channel ENaC.Abbreviation: n.r., not reported.bGreatest decrease observed in the youngest mice.cStudied in cultured foetal tracheal cells.

  • Further studies using Cftrtm1Hgu mice have demonstratedsignificantly impaired mucociliary transport of inert par-ticles in vivo (Ref. 19) and an altered distribution of mucusand antimicrobial airway surface liquid (ASL)-secreting sub-mucosal glands20 suggesting possible mechanisms fordisease development, secondary to CFTR dysfunction. Asubsequent study using embedded, cultured lung slicesfrom mice homozygous for the Cftrtm1Unc mutation, par-tially backcrossed onto the C57Bl/6 background, alsodemonstrated impaired mucociliary transport21.

    Although these studies provide evidence of an abnormalresponse to bacterial burden, initial studies examining theeffect of exposure to the classic lung pathogen Pseudomonasaeruginosa failed to demonstrate any abnormal lung pheno-type in Cftrtm1Hgu/Cftrtm1Hgu mice (Larbig, M. et al., Pseudomonasaeruginosa infection in cystic fibrosis: animal model of thetransgenic cftrm1HGU mouse. European Cystic Fibrosis con-ference, 1319 June 1998, Berlin), Cftrtm1Unc/Cftrtm1Unc mice18

    or Cftrtm1Kth/Cftrtm1Kth mice (carrying the F508 mutation)22.These studies suggested that, despite abnormal responsesto other bacteria, mouse models of CF might not displayincreased susceptibility to pulmonary infection withP. aeruginosa. This is obviously a significant contrast to CFlung disease in humans, the explanation for which remainselusive. However, a recent study examining the in vivo sig-nificance of epithelial cell internalization of P. aeruginosa

    quantified and localized these organisms within a fewhours after delivery23. Under the conditions of this study,significant differences were observed between variousmouse models of CF and controls, suggesting that basicdefects in the host interaction with this organism mightindeed exist in the mouse models, despite the elusive natureof convincing pathology.

    The study of P. aeruginosa in mouse models of CF isprobably complicated by the phenotypic alteration that thisorganism undergoes over the course of chronic infectionof the lungs of CF individuals. Although the initial infec-tions in CF individuals are with planktonic strains, rapiddeterioration of the CF lung usually occurs after transfor-mation of P. aeruginosa into the mucoid form in the host. Itis therefore unclear whether the most revealing studieswill arise from trying to mimic this process by challengingmice with non-mucoid P. aeruginosa to evaluate predispositionto infection, or modeling colonization with mucoidstrains in the absence of previous rounds of infection. Inaddition, the significance of previous infections with otherorganisms, and the consequent antibacterial chemotherapyreceived, is unclear with respect to priming the CF lungfor P. aeruginosa infection.

    To date, studies using agar beads laden with P. aeruginosato model colonization have been more successful than thealternative approach. Using this technique, significantly

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    Review | A TRENDS Guide to Mouse Models of Human Diseases TRENDS in Genetics, Vol.17 No.10, October 2001

    Table 6. Lung phenotypes in mouse models of cystic fibrosisa

    Mutation Observation Refs

    Cftrtm1Hgu Pulmonary clearance of Staphylococcus aureus and Burkholderia cepacia 15 Pulmonary pathology after repeated exposure to S. aureus and B. cepacia 15 Bronchoalveolar lavage tumour necrosis factor 16 Inflammatory cells in tracheal lamina propria 19 Tracheal mucociliary transport 19 Pulmonary clearance of Pseudomonas aeruginosa b

    Altered submucosal gland distribution 20

    Cftrtm1G551D S100 Ca2+ binding protein and tumour necrosis factor 53Cftrtm1Unc Pulmonary clearance and pulmonary pathology after repeated exposure to B. cepacia 17

    Pulmonary clearance of P. aeruginosa and S. aureus 18

    Airway mucociliary transport 21 Mortality from P. aeruginosa-laden agar beads 25Cytokine abnormalities 24

    iNOS expression 29Cftrtm1Kth Pulmonary clearance of P. aeruginosa 22

    Lung cell ingestion, lung burden with P. aeruginosa 23 iNOS expression 28

    aComparison of the pulmonary pathology observed in different mouse models of cystic fibrosis (CF). Observations:, increased; , decreased; , no change in comparison to non-CF controls.bLarbig, M. et al., Pseudomonas aeruginosa infection in cystic fibrosis: animal model of the transgenic cftrm1HGUmouse. European Cystic Fibrosis Conference, 1319 June 1998, Berlin.

  • decreased survival rates have been demonstrated inCftrtm1Unc/Cftrtm1Unc mice24,25; however, the basis for this ob-servation is unclear. Bacterial proliferation was demon-strated regardless of genotype, only one of the studies re-covered significantly higher numbers of bacteria fromthe lungs of mutant mice, and no significant differencesin lung histopathology were observed between mutantmice and non-CF littermates. Perhaps the most significantobservations were the significantly higher levels of pro-inflammatory cytokines and the decreased levels of theanti-inflammatory cytokine IL-10 in Cftrtm1Unc/Cftrtm1Unc mice,despite an absence of significant differences in the bacteriallung burden or pulmonary histopathology24. The role ofthe liquid diet fed to the mice in these studies could,however, prove to be significant, with a malnourishedmouse model reported to demonstrate some strikingsimilarities26. Nevertheless, the agar bead model revealsinteresting phenotypic differences between mouse modelsof CF and control animals, and could prove effective in thestudy of the host response to established infection. Thismodel has since been used in the further development ofadenoviral-mediated gene transfer27.

    A further phenotype described in mouse models ofCF is that of decreased pulmonary levels of the inducibleisoform of nitric oxide synthase (iNOS), which has beenimplicated in the development of CF lung disease.The ex-pression of iNOS is significantly reduced in mixed back-ground strain Cftrtm1Kth/Cftrtm1Kth mice, homozygous for theF508 mutation28, and Cftrtm1Unc/Cftrtm1Unc mice29. Further-more, in Cftrtm1Unc/Cftrtm1Unc mice expressing human CFTRcDNA in the intestinal tract but not the nose, iNOS expres-sion is observed in the ileum but not in the nasal epi-thelium29. The exact mechanism by which CFTR affectsthe expression of iNOS remains to be determined.

    In conclusion, despite some significant similaritiesbetween CF lung disease in humans and mouse modelsof CF and promising recent developments17,23, significantdifferences are also evident under the experimental con-ditions described, and the suitability of these models asendpoints for therapeutic testing remains controversial.

    Testing hypotheses in mouse models of cystic fibrosisDespite certain differences between the pathology observedin mouse models of CF and human CF individuals, theformer clearly demonstrate a range of abnormal pheno-types as a result of Cftr mutation. Consequently, mousemodels of CF have been used to perform in vivo analysis ofseveral hypotheses describing the pathogenesis of CF thatwere generated primarily on the basis of in vitro studies.

    Recent hypotheses have emphasized the role of CFTR indetermining either the volume or the ionic concentrationof the ASL lining in the lung epithelia, affecting mucociliaryclearance or the antibacterial activity of salt-sensitivepeptides30. Contrasting hypotheses were established onthe basis of in vitro studies and limited analysis of human

    ASL. Several studies have circumvented some of the com-plicating factors by measuring the ionic composition ofASL in airways of various mouse models of CF, usingtechniques that could not be performed in human sub-jects3134. Although the results of these studies suggestthat Cftr mutation does not affect ASL salt concentration,they conflict over the in vivo tonicity. However, these stud-ies used contrasting techniques on mouse models of CFwith different mutations in Cftr, on different backgroundstrains. All these potential influences, and others (e.g. therole and distribution of submucosal glands) can be con-trolled for, and altered, in future studies.Thus, the crucialfactors influencing data from mouse model studies shouldbe more easily addressed in future studies and providein vivo answers to the questions raised by these hypotheses.In addition, lines of transgenic mice with knockout mu-tations in genes encoding antibacterial peptides havebeen established and are currently being characterized.Theanalysis of these mutant mice and the offspring inter-crossed with mouse models of CF will help to determine therole of these antibacterial agents in the lung, particularlywith reference to CF lung disease.

    Mouse models of CF have also been used to examinethe hypothesis that CFTR is a receptor for P. aeruginosacomplete lipopolysaccharide core, resulting in bacterialinternalization into epithelial cells. This mechanism hasbeen proposed to perform a protective role in the normallung and to be compromised in CF (Ref. 35). A recentstudy examined the host interaction with P. aeruginosa just4.5 hours after bacterial delivery23.This study demonstratedsignificantly less ingestion of P. aeruginosa by lung cells andsignificantly greater bacterial lung burdens in variousmouse models of CF compared to wt controls. Confocaland scanning electron microscopic imaging was used todemonstrate association between airway epithelial cellsand bacteria in the wt controls, suggesting a possible rolefor these cells in host defense. By contrast, a study using arange of transgenic mice expressing varying levels ofhuman and murine CFTR found no direct correlation be-tween the level of CFTR expression and the pulmonaryclearance of P. aeruginosa, or the association of bacteria withepithelial cells in vivo (Ref. 36). The time points and thechoice of strains evaluated in these studies appear to becrucial23, however, emphasizing the requirement for rig-orous evaluation in optimization of these phenotypes andperhaps the subtlety of the underlying defect.

    Mouse models of CF have also been used to examinepossible hypotheses for the high frequency of the mutant CFallele in human Caucasian populations.These studies havesuggested two possible heterozygote advantage theories.In Cftrtm1Unc/Cftrtm1Unc mice, expressing no Cftr, intestinalfluid secretion was not observed in response to choleratoxin, and in heterozygote mice secretion was reduced to50% of normal wt levels37. This suggests that individualscarrying a mutant CF allele might be more resistant tothe potentially fatal diarrhea and dehydration induced by

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    TRENDS in Genetics, Vol.17 No.10, October 2001 A TRENDS Guide to Mouse Models of Human Diseases | Review

  • Vibrio cholerae.A later study demonstrated that homozygousand heterozygous Cftrtm2Cam mice were protected from intestinal epithelial invasion by Salmonella typhii, lendingcredence to the idea that mutant CF alleles might confer aresistance to typhoid fever38.

    Thus, the ability to pursue invasive techniques in vivoand to control for genetic and environmental influencesin future studies makes mouse models of CF a powerfulsystem to help dissect the pathogenesis of CF lung disease and define many of the critical components ofdisease development.

    Future directionsThe challenges for future use of mouse models of CFinitially lie in refining existing models to replicate humandisease as accurately as possible and then in under-standing the mechanisms that underlie the developmentof the mutant phenotypes observed only in mice. Thephenotypic variability observed in mouse models of CFas a result of different strain backgrounds, specific mu-tations in Cftr, and environmental influences, is of greatpotential for the definition of genetic modifiers and torefine the mouse models of CF. These processes shoulddefine many of the key components involved in diseasepathogenesis, establish the most suitable models fortherapy testing with clear relevant clinical endpoints, andsuggest novel therapeutic approaches for the treatment ofhuman disease.The future availability of comprehensivegene expression arrays could prove particularly illumi-nating in studying the mechanisms underlying the pheno-typic differences observed between different models,and between mouse models of CF and non-CF littermates,in response to different environmental stimuli. By adopt-ing such an approach, mouse models of CF can providevaluable contributions to our understanding of this dis-ease process and support efforts towards organ-basedtreatment for CF patients.

    AcknowledgementsWe gratefully acknowledge Julia R. Dorin, David J. Porteous,Eric W.F.W. Alton and Steve Smith. Donald Davidson is aWellcome Trust fellow. Mark Rolfe is supported by theMedical Research Council, UK.

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    TRENDS in Genetics, Vol.17 No.10, October 2001 A TRENDS Guide to Mouse Models of Human Diseases | Review

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