Pathophysiology of Gene-Targeted Mouse Models for Cystic Fibrosis

1999 ◽  
Vol 79 (1) ◽  
pp. S193-S214 ◽  
Author(s):  
BARBARA R. GRUBB ◽  
RICHARD C. BOUCHER
Keyword(s):  
Cystic Fibrosis ◽  
Ion Transport ◽  
Gene Targeting ◽  
Mouse Models ◽  
Genetic Background ◽  
Murine Models ◽  
Disease Phenotype ◽  
Fatal Disease ◽  
Gastrointestinal Tissue ◽  
Unexpected Findings

Grubb, Barbara R., and Richard C. Boucher. Pathophysiology of Gene-Targeted Mouse Models for Cystic Fibrosis. Physiol. Rev. 79, Suppl.: S193–S214, 1999. — Mutations in the gene causing the fatal disease cystic fibrosis (CF) result in abnormal transport of several ions across a number of epithelial tissues. In just 3 years after this gene was cloned, the first CF mouse models were generated. The CF mouse models generated to date have provided a wealth of information on the pathophysiology of the disease in a variety of organs. Heterogeneity of disease in the mouse models is due to the variety of gene-targeting strategies used in the generation of the CF mouse models as well as the diversity of the murine genetic background. This paper reviews the pathophysiology in the tissues and organs (gastrointestinal, airway, hepatobiliary, pancreas, reproductive, and salivary tissue) involved in the disease in the various CF mouse models. Marked similarities to and differences from the human disease have been observed in the various murine models. Some of the CF mouse models accurately reflect the ion-transport abnormalities and disease phenotype seen in human CF patients, especially in gastrointestinal tissue. However, alterations in airway ion transport, which lead to the devastating lung disease in CF patients, appear to be largely absent in the CF mouse models. Reasons for these unexpected findings are discussed. This paper also reviews pharmacotherapeutic and gene therapeutic studies in the various mouse models.

scholarly journals Genetically Altered Mouse Models: the Good, the Bad, and the Ugly

2003 ◽  
Vol 14 (3) ◽  
pp. 154-174 ◽  
Author(s):  
Tamizchelvi Thyagarajan ◽  
Satish Totey ◽  
Mary Jo S. Danton ◽  
Ashok B. Kulkarni
Keyword(s):  
Gene Targeting ◽  
Mouse Models ◽  
Molecular Mechanisms ◽  
Gene Knockout ◽  
Genetically Engineered ◽  
Murine Models ◽  
Functional Roles ◽  
Targeted Gene Disruption ◽  
Gene Knockout Mouse

Targeted gene disruption in mice is a powerful tool for generating murine models for human development and disease. While the human genome program has helped to generate numerous candidate genes, few genes have been characterized for their precise in vivo functions. Gene targeting has had an enormous impact on our ability to delineate the functional roles of these genes. Many gene knockout mouse models faithfully mimic the phenotypes of the human diseases. Because some models display an unexpected or no phenotype, controversy has arisen about the value of gene-targeting strategies. We argue in favor of gene-targeting strategies, provided they are used with caution, particularly in interpreting phenotypes in craniofacial and oral biology, where many genes have pleiotropic roles. The potential pitfalls are outweighed by the unique opportunities for developing and testing different therapeutic strategies before they are introduced into the clinic. In the future, we believe that genetically engineered animal models will be indispensable for gaining important insights into the molecular mechanisms underlying development, as well as disease pathogenesis, diagnosis, prevention, and treatment.

Intestinal physiology and pathology in gene-targeted mouse models of cystic fibrosis

1997 ◽  
Vol 273 (2) ◽  
pp. G258-G266 ◽  
Author(s):  
B. R. Grubb ◽  
S. E. Gabriel
Keyword(s):  
Cystic Fibrosis ◽  
Ion Transport ◽  
Mouse Models ◽  
Intestinal Tract ◽  
Genetic Disorder ◽  
Distal Colon ◽  
Airway Disease ◽  
Protein Product ◽  
Heterozygote Advantage ◽  
Intestinal Physiology

Cystic fibrosis (CF) is a fatal genetic disorder that affects approximately 1 in 2,500 live Caucasian births. The disease can be described as a generalized exocrine disease affecting a variety of epithelial tissues, with early manifestation as meconium ileus in a significant number of neonates. Cloning of the gene causing CF was accomplished in 1989, and the protein product, cystic fibrosis transmembrane conductance regulator (CFTR), has been conclusively shown to be an adenosine 3',5'-cyclic monophosphate (cAMP)-regulated Cl- channel. Subsequently, several mouse models of CF were generated by gene-targeting approaches in an attempt to further understand this disease. The initial excitement generated by the emergence of these mouse models was somewhat tempered by the finding that none of the models developed airway disease, which is currently responsible for most of the morbidity and mortality in the human CF population. However, the various CF mouse models, of which there are now 10, are remarkably similar to their human counterparts with respect to intestinal pathophysiology. Most importantly, the intestinal tract of the CF mouse models demonstrates the absence of cAMP-mediated Cl- transport, which is a hallmark of CF disease. Furthermore, the murine CF intestinal tract also shows an inability to secrete HCO3-, defective cAMP regulation of electroneutral NaCl absorption, and elevated electrogenic Na+ transport in the distal colon, as well as other ion transport perturbations. Besides the fundamental mechanisms of ion transport studied in the murine CF intestinal tract, these models have also been important in understanding other tissues with regard to CF. Mice heterozygous for the CFTR knockout gene have a reduced ability to secret Cl- and fluid and therefore provide further support for the CF "heterozygote advantage" hypothesis. Some CF mouse models maintain a limited ability to secrete Cl-, which may be due to accessory genes that are hypothesized to ameliorate disease severity in the intestines of these mice. This review describes the CF models generated and compares the murine defects in ion transport with observed abnormalities in the human CF intestine.

Murine models susceptibility to distinctTrypanosoma cruziI genotypes infection

Parasitology ◽  
2016 ◽  
Vol 144 (4) ◽  
pp. 512-519 ◽  
Author(s):  
CIELO M. LEÓN ◽  
MARLENY MONTILLA ◽  
RICARDO VANEGAS ◽  
MARIA CASTILLO ◽  
EDGAR PARRA ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Mouse Models ◽  
Genetic Background ◽  
Murine Models ◽  
Survival Curves ◽  
Disease Pathogenesis ◽  
Phylogenetic Studies ◽  
History Of ◽  
Kinetoplastid Parasite

SUMMARYChagas disease is a complex zoonosis that affects around 8 million people worldwide. This pathology is caused byTrypanosoma cruzi, a kinetoplastid parasite that shows tremendous genetic diversity evinced in six distinct Discrete Typing Units (TcI-TcVI) including a recent genotype named as TcBat and associated with anthropogenic bats. TcI presents a broad geographical distribution and has been associated with chronic cardiomyopathy. Recent phylogenetic studies suggest the existence of two genotypes (Domestic (TcIDom) and sylvatic TcI) within TcI. The understanding of the course of the infection in different mouse models by these two genotypes is not yet known. Therefore, we infected 126 animals (ICR-CD1, National Institute of Health (NIH) and Balb/c) with two TcIDomstrains and one sylvatic strain for a follow-up period of 60 days. We quantified the parasitaemia, immune response and histopathology observing that the maximum day of parasitaemia was achieved at day 21 post-infection. Domestic strains showed higher parasitaemia than the sylvatic strain in the three mouse models; however in the survival curves Balb/c mice were less susceptible to infection compared with NIH and ICR-CD1. Our results suggest that the genetic background plays a fundamental role in the natural history of the infection and the sympatric TcI genotypes have relevant implications in disease pathogenesis.

scholarly journals Resolvin D1 regulates epithelial ion transport and inflammation in cystic fibrosis airways

2018 ◽  
Vol 17 (5) ◽  
pp. 607-615 ◽  
Author(s):  
Fiona C. Ringholz ◽  
Gerard Higgins ◽  
Aurélie Hatton ◽  
Ali Sassi ◽  
Ahmad Moukachar ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Ion Transport ◽  
Resolvin D1 ◽  
Epithelial Ion Transport

scholarly journals Targeted Drug Delivery Technologies Potentiate the Overall Therapeutic Efficacy of an Indole Derivative in a Mouse Cystic Fibrosis Setting

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1601
Author(s):  
Matteo Puccetti ◽  
Marilena Pariano ◽  
Giorgia Renga ◽  
Ilaria Santarelli ◽  
Fiorella D’Onofrio ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Targeted Drug Delivery ◽  
Fungal Infections ◽  
Murine Models ◽  
Multisystem Disease ◽  
Aryl Hydrocarbon ◽  
Target Organs ◽  
Infection And Inflammation ◽  
Anti Inflammatory ◽  
Inflammatory Toxicity

Inflammation plays a major role in the pathophysiology of cystic fibrosis (CF), a multisystem disease. Anti-inflammatory therapies are, therefore, of interest in CF, provided that the inhibition of inflammation does not compromise the ability to fight pathogens. Here, we assess whether indole-3-aldehyde (3-IAld), a ligand of the aryl hydrocarbon receptor (AhR), may encompass such an activity. We resorted to biopharmaceutical technologies in order to deliver 3-IAld directly into the lung, via dry powder inhalation, or into the gut, via enteric microparticles, in murine models of CF infection and inflammation. We found the site-specific delivery of 3-IAld to be an efficient strategy to restore immune and microbial homeostasis in CF organs, and mitigate lung and gut inflammatory pathology in response to fungal infections, in the relative absence of local and systemic inflammatory toxicity. Thus, enhanced delivery to target organs of AhR agonists, such as 3-IAld, may pave the way for the development of safe and effective anti-inflammatory agents in CF.

Nitric oxide has no beneficial effects on ion transport defects in cystic fibrosis human nasal epithelium

2000 ◽  
Vol 441 (1) ◽  
pp. 133-137 ◽  
Author(s):  
Claudia Rückes-Nilges ◽  
H. Lindemann ◽  
Thorsten Klimek ◽  
Hiltrud Glanz ◽  
Wolf-Michael Weber
Keyword(s):  
Nitric Oxide ◽  
Cystic Fibrosis ◽  
Ion Transport ◽  
Nasal Epithelium ◽  
Beneficial Effects ◽  
Human Nasal Epithelium

Pharmacological modulation of ion transport across wild-type and ΔF508 CFTR-expressing human bronchial epithelia

2000 ◽  
Vol 279 (2) ◽  
pp. C461-C479 ◽  
Author(s):  
Daniel C. Devor ◽  
Robert J. Bridges ◽  
Joseph M. Pilewski
Keyword(s):  
Cystic Fibrosis ◽  
Ion Transport ◽  
Short Circuit ◽  
Primary Cultures ◽  
Short Circuit Current ◽  
Bronchial Epithelium ◽  
Disulfonic Acid ◽  
Wild Type ◽  
Pharmacological Agents ◽  
Transport Defect

Forskolin, UTP, 1-ethyl-2-benzimidazolinone (1-EBIO), NS004, 8-methoxypsoralen (Methoxsalen; 8-MOP), and genistein were evaluated for their effects on ion transport across primary cultures of human bronchial epithelium (HBE) expressing wild-type (wt HBE) and ΔF508 (ΔF-HBE) cystic fibrosis transmembrane conductance regulator. In wt HBE, the baseline short-circuit current ( I sc) averaged 27.0 ± 0.6 μA/cm2 ( n = 350). Amiloride reduced this I sc by 13.5 ± 0.5 μA/cm2 ( n = 317). In ΔF-HBE, baseline I sc was 33.8 ± 1.2 μA/cm2 ( n = 200), and amiloride reduced this by 29.6 ± 1.5 μA/cm2 ( n = 116), demonstrating the characteristic hyperabsorption of Na+ associated with cystic fibrosis (CF). In wt HBE, subsequent to amiloride, forskolin induced a sustained, bumetanide-sensitive I sc(Δ I sc = 8.4 ± 0.8 μA/cm2; n = 119). Addition of acetazolamide, 5-( N-ethyl- N-isopropyl)-amiloride, and serosal 4,4′-dinitrostilben-2,2′-disulfonic acid further reduced I sc, suggesting forskolin also stimulates HCO3 − secretion. This was confirmed by ion substitution studies. The forskolin-induced I scwas inhibited by 293B, Ba2+, clofilium, and quinine, whereas charybdotoxin was without effect. In ΔF-HBE the forskolin I sc response was reduced to 1.2 ± 0.3 μA/cm2 ( n = 30). In wt HBE, mucosal UTP induced a transient increase in I sc (Δ I sc = 15.5 ± 1.1 μA/cm2; n = 44) followed by a sustained plateau, whereas in ΔF-HBE the increase in I sc was reduced to 5.8 ± 0.7 μA/cm2 ( n = 13). In wt HBE, 1-EBIO, NS004, 8-MOP, and genistein increased I sc by 11.6 ± 0.9 ( n = 20), 10.8 ± 1.7 ( n = 18), 10.0 ± 1.6 ( n = 5), and 7.9 ± 0.8 μA/cm2( n = 17), respectively. In ΔF-HBE, 1-EBIO, NS004, and 8-MOP failed to stimulate Cl− secretion. However, addition of NS004 subsequent to forskolin induced a sustained Cl−secretory response (2.1 ± 0.3 μA/cm2, n = 21). In ΔF-HBE, genistein alone stimulated Cl− secretion (2.5 ± 0.5 μA/cm2, n = 11). After incubation of ΔF-HBE at 26°C for 24 h, the responses to 1-EBIO, NS004, and genistein were all potentiated. 1-EBIO and genistein increased Na+ absorption across ΔF-HBE, whereas NS004 and 8-MOP had no effect. Finally, Ca2+-, but not cAMP-mediated agonists, stimulated K+ secretion across both wt HBE and ΔF-HBE in a glibenclamide-dependent fashion. Our results demonstrate that pharmacological agents directed at both basolateral K+ and apical Cl− conductances directly modulate Cl−secretion across HBE, indicating they may be useful in ameliorating the ion transport defect associated with CF.

scholarly journals A preclinical ultrasound method for the assessment of vascular disease progression in murine models

Ultrasound ◽  
2018 ◽  
Vol 27 (2) ◽  
pp. 85-93
Author(s):  
Justyna Janus ◽  
Baris Kanber ◽  
Wadhah Mahbuba ◽  
Charlotte Beynon ◽  
Kumar V Ramnarine ◽  
...  
Keyword(s):  
Image Processing ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Vascular Disease ◽  
Mouse Models ◽  
Murine Models ◽  
Analysis Method ◽  
Manual Analysis ◽  
Abdominal Aortic ◽  
Automatic Image Processing

Introduction The efficacy of preclinical ultrasound at providing a quantitative assessment of mouse models of vascular disease is relatively unknown. In this study, preclinical ultrasound was used in combination with a semi-automatic image processing method to track arterial distension alterations in mouse models of abdominal aortic aneurysm and atherosclerosis. Methods Longitudinal B-mode ultrasound images of the abdominal aorta were acquired using a preclinical ultrasound scanner. Arterial distension was assessed using a semi-automatic image processing algorithm to track vessel wall motion over the cardiac cycle. A standard, manual analysis method was applied for comparison. Results Mean arterial distension was significantly lower in abdominal aortic aneurysm mice between day 0 and day 7 post-onset of disease (p < 0.01) and between day 0 and day 14 (p < 0.001), while no difference was observed in sham control mice. Manual analysis detected a significant decrease (p < 0.05) between day 0 and day 14 only. Atherosclerotic mice showed alterations in arterial distension relating to genetic modification and diet. Arterial distension was significantly lower (p < 0.05) in Ldlr−/− (++/−−) mice fed high-fat western diet when compared with both wild type (++/++) mice and Ldlr−/− (++/−−) mice fed chow diet. The manual method did not detect a significant difference between these groups. Conclusions Arterial distension can be used as an early marker for the detection of arterial disease in murine models. The semi-automatic analysis method provided increased sensitivity to differences between experimental groups when compared to the manual analysis method.

Sign in / Sign up

Export Citation Format

Share Document