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PubMed2006

A mouse model for monitoring calpain activity under physiological and pathological conditions.

Calpains are Ca(2+)-dependent cysteine proteases known to be important for the regulation of cell functions and which aberrant activation causes cell death in a number of degenerative disorders. To provide a tool for monitoring the status of calpain activity in vivo under physiological and pathological conditions, we created a mouse model that expresses ubiquitously a fluorescent reporter consisting of eCFP and eYFP separated by a linker cleavable by the ubiquitous calpains. We named this mouse CAFI for calpain activity monitored by FRET imaging. Our validation studies demonstrated that the level of calpain activity correlates with a decrease in FRET (fluorescence resonance energy transfer) between the two fluorescent proteins. Using this model, we observed a small level of activity after denervation and fasting, a high level of activity during muscle regeneration and ischemia, and local activity in damaged myofibers after exercise. Finally, we crossed the CAFI mouse with the alpha-sarcoglycan-deficient model, demonstrating an increase of calpain activity at the steady state. Altogether, our results present evidence that CAFI mice could be a valuable tool in which to follow calpain activity at physiological levels and in disease states.

Animals↗
PubMed1995

A mouse model for the cystic fibrosis delta F508 mutation.

Most cystic fibrosis (CF) patients produce a mutant form (delta F508) of the cystic fibrosis transmembrane conductance regulator (CFTR), which is not properly processed in normal cells but is active as a chloride channel in several experimental systems. We used a double homologous recombination ('Hit and Run') procedure to generate a mouse model for the delta F508 mutation. Targeted embryonic stem (ES) cells (Hit clones) were found; of these either 80 or 20% of the clones had lost the delta F508 mutation, depending on the distance between the linearization site in the targeting construct and the delta F508 mutation. Correctly targeted clones underwent a second selection step resulting in ES cell clones (Run clones) heterozygous for the delta F508 mutation with an efficiency of 2-7%. Chimeric mice were generated and offspring homozygous for the delta F508 mutation showed electrophysiological abnormalities in nasal epithelium, gallbladder and in the intestine, and histological abnormalities in the intestine, typical of CF. Our data suggest that the delta F508 mice have residual delta F508 CFTR activity which would explain the mild pathology of the delta F508 mice. The delta F508 mouse may provide a useful model for the study of the processing defect of delta F508 CFTR and for the development of novel therapeutic approaches based on circumvention of the processing block.

Animals↗
PubMed2004

A new mouse model of type 2 diabetes, produced by N-ethyl-nitrosourea mutagenesis, is the result of a missense mutation in the glucokinase gene.

Here we report the first cloned N-ethyl-nitrosourea (ENU)-derived mouse model of diabetes. GENA348 was identified through free-fed plasma glucose measurement, being more than 2 SDs above the population mean of a cohort of >1,201 male ENU mutant mice. The underlying gene was mapped to the maturity-onset diabetes of the young (MODY2) homology region of mouse chromosome 11 (logarithm of odds 6.0). Positional candidate gene analyses revealed an A to T transversion mutation in exon 9 of the glucokinase gene, resulting in an isoleucine to phenylalanine change at amino acid 366 (I366F). Heterozygous mutants have 67% of the enzyme activity of wild-type littermates (P < 0.0012). Homozygous mutants have less enzyme activity (14% of wild-type activity) and are even less glucose tolerant. The GENA348 allele is novel because no mouse or human diabetes studies have described a mutation in the corresponding amino acid position. It is also the first glucokinase missense mutation reported in mice and is homozygous viable, unlike the global knockout mutations. This work demonstrates that ENU mutagenesis screens can be used to generate models of complex phenotypes, such as type 2 diabetes, that are directly relevant to human disease.

Adenine↗
PubMed1998

New in situ mouse model to quantify alveolar epithelial fluid clearance.

Because the availability of transgenic mice makes it possible to examine the contribution of single genes to in vivo function, we developed a simple in situ mouse model that can be used to quantify isosmolar alveolar epithelial fluid clearance (AFC). Mice were killed, a tracheostomy was done, and then a test solution of a 5% isosmolar albumin solution with 0.1 micro Ci of 125I-labeled albumin was instilled via the trachea into the distal air spaces of both lungs. After instillation, the lungs were inflated to 7 cmH2O with 100% O2 and maintained at 37 degrees C by placing the animals under an infrared lamp. AFC was measured by the progressive increase in concentration of labeled and unlabeled protein over 1 h. The results indicated the following. 1) Basal, unstimulated AFC in mouse lungs was significantly faster than in ex vivo rat lungs (27 +/- 5% in in situ mice vs. 11 +/- 3% in ex vivo rat lungs; P < 0.05). 2) Comparison of equivalent doses (10(-4) M) of beta-adrenergic agonist (isoproterenol) and beta2-adrenergic agonists (terbutaline and salmeterol) indicated that stimulated clearance occurred only in presence of isoproterenol. 3) Because atenolol, a specific beta1-antagonist, abolished the effect of isoproterenol, the beta-adrenergic stimulation appears to be mediated by beta1-receptors. The rate of AFC in nonperfused mouse lungs was significantly faster than in prior studies of nonperfused lungs in rats and sheep. Interestingly, the stimulated clearance rate in mice was similar to the fast rates of AFC that we recently reported in patients recovering from hydrostatic pulmonary edema. This in situ model is a unique experimental preparation that can be readily used to quantify isosmolar epithelial fluid clearance in mice.

Adrenergic beta-Agonists↗
PubMed2004

A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression.

Migraine is a common, disabling, multifactorial, episodic neurovascular disorder of unknown etiology. Familial hemiplegic migraine type 1 (FHM-1) is a Mendelian subtype of migraine with aura that is caused by missense mutations in the CACNA1A gene that encodes the alpha(1) subunit of neuronal Ca(v)2.1 Ca(2+) channels. We generated a knockin mouse model carrying the human pure FHM-1 R192Q mutation and found multiple gain-of-function effects. These include increased Ca(v)2.1 current density in cerebellar neurons, enhanced neurotransmission at the neuromuscular junction, and, in the intact animal, a reduced threshold and increased velocity of cortical spreading depression (CSD; the likely mechanism for the migraine aura). Our data show that the increased susceptibility for CSD and aura in migraine may be due to cortical hyperexcitability. The R192Q FHM-1 mouse is a promising animal model to study migraine mechanisms and treatments.

Animals↗
PubMed2025

Development of a new flippase-dependent mouse model for red fluorescence-based isolation of KRASG12D oncogene-expressing tumor cells.

Proto-oncogene KRAS, GTPase (KRAS) is one of the most intensively studied oncogenes in cancer research. Although several mouse models allow for regulated expression of mutant KRAS, selective isolation and analysis of transforming or tumor cells that produce the KRAS oncogene remains a challenge. In our study, we present a knock-in model of oncogenic variant KRASG12D that enables the "activation" of KRASG12D expression together with production of red fluorescent protein tdTomato. Both proteins are expressed from the endogenous Kras locus after recombination of a transcriptional stop box in the genomic DNA by the enzyme flippase (Flp). We have demonstrated the functionality of the allele termed RedRas (abbreviated KrasRR) under in vitro conditions with mouse embryonic fibroblasts and organoids and in vivo in the lung and colon epithelium. After recombination with adenoviral vectors carrying the Flp gene, the KrasRR allele itself triggers formation of lung adenomas. In the colon epithelium, it causes the progression of adenomas that are triggered by the loss of tumor suppressor adenomatous polyposis coli (APC). Importantly, cells in which recombination has successfully occurred can be visualized and isolated using the fluorescence emitted by tdTomato. Furthermore, we show that KRASG12D production enables intestinal organoid growth independent of epidermal growth factor (EGF) signaling and that the KRASG12D function is effectively suppressed by specific inhibitor MRTX1133.

Animals↗
PubMed2005

The effect of DNA repair defects on reproductive performance in nucleotide excision repair (NER) mouse models: an epidemiological approach.

In this study, we used an epidemiological approach to analyze an animal database of DNA repair deficient mice on reproductive performance in five Nucleotide Excision Repair (NER) mutant mouse models on a C57BL/6 genetic background, namely CSA, CSB, XPA, XPC [models for the human DNA repair disorders Cockayne Syndrome (CS) and xeroderma pigmentosum (XP), respectively] and mHR23B (not associated with human disease). This approach allowed us to detect and quantify reproductive effects based on a relatively small number of matings. We measured and quantified the scale of the effect between factors that might influence reproductive performance (i.e. age at co-housing, seasons) and reproductive parameters (i.e. litter size and pairing-to-birth interval -'pbi'). Besides, we detected and quantified the differences in reproductive performance between wild type mice and heterozygous/homozygous NER mutant mice. From our analyses, we found impaired reproduction in heterozygous and homozygous knock out mice; in particular, reduced litter size and lengthened pbi was related to the NER mutation-mHR23B, in heterozygous couples, even if they were otherwise phenotypically normal. Heterozygous mHR23B couples produced a 6.6-fold lower number of mHR23B(-/-) pups than indicated by Mendelian expectation; other genetic deficiencies studied were not statistically significant from each other or wild type controls. We concluded that careful epidemiological evaluations by analysis of animal database could provide reliable information on reproductive performance and detect deviations that would remain unnoticed without this. Also, some managerial aspects of mouse breeding could be evaluated.

Animals↗
PubMed2006

Mouse models of autism spectrum disorders: the challenge for behavioral genetics.

Autism is a severe neurodevelopmental disorder, which typically emerges early in childhood. The core symptoms of autism include deficits in social interaction, impaired communication, and aberrant repetitive behavior, including self-injury. Despite the strong genetic component for the disease, most cases of autism have not been linked to mutations in a specific gene, and the etiology of the disorder has yet to be established. At the present time, there is no generally accepted therapeutic strategy to treat the core symptoms of autism, and there remains a critical need for appropriate animal models and relevant behavioral assays to promote the understanding and treatment of the clinical syndrome. Challenges for the development of valid mouse models include complex genetic interactions underlying the high heritability of the disease in humans, diagnosis based on deficits in social interaction and communication, and the lack of confirmatory neuropathological markers to provide validation for genetic models of the disorder. Research focusing on genes that mediate social behavior in mice may help identify neural circuitry essential for normal social interaction, and lead to novel genetic animal models of the autism behavioral phenotype.

Animals↗
PubMed2003

Transgenic mouse models of dopamine deficiency.

The dopamine system is implicated in several neurological and psychiatric disorders. Genetic mutations or variations that affect dopamine system functions either directly cause or contribute to these disorders, even though other genetic and environmental factors may contribute significantly to some of these disorders as well. Transgenic mice increasingly become important tools in revealing functions of genes that are essential components of the dopamine system as well as in modeling human genetic disorders. We have reviewed a comprehensive list of those genes and compared genetic mutations/variations in humans and transgenic mouse models. The significance and limitations of these animal models as well as future directions are discussed.

Animals↗
PubMed2006

Pathogenesis of myelofibrosis with myeloid metaplasia: Insight from mouse models.

Myelofibrosis with myeloid metaplasia or idiopathic myelofibrosis is a myeloproliferative disease. It is known to be a stem-cell disorder that leads to a secondary and reactive stromal reaction in the bone marrow microenvironment that is responsible for impaired haematopoiesis. Although progress has been made in the elucidation of the pathogenesis of idiopathic myelofibrosis, lack of suitable models has limited our understanding of the pathology. The aim of this chapter is to address recent inferred new insights in mouse models into the pathogenesis of osteomyelofibrosis. These insights outline the role of transforming growth factor-beta1 and osteoprotegerin in the promotion of myelofibrosis and osteosclerosis, respectively, paying special regard to the role of abnormal megakaryocyte proliferation and maturation.

Animals↗
PubMed2004

Techniques: species' finest blend--humanized mouse models in inflammatory skin disease research.

Differences between humans and mice often hamper the transfer of promising results from the bench to the clinic. For ethical reasons, research that involves patients is limited, and so there is an urgent need for models that mimic the human situation as closely as possible. In recent years, there has been considerable progress in generating humanized mouse models, and their application to drug discovery has proved fruitful. So, how can mice be humanized, and how can humanized mice be employed in immunology research and drug discovery? In this article, we answer these questions, focusing on T-cell-mediated skin diseases as an example.

Animals↗
PubMed1998

The correlation of telomerase and IL-10 with leukemia transformation in a mouse model of chronic lymphocytic leukemia (CLL).

Telomerase activity is upregulated in activated and malignant lymphocytes. We studied the correlation of telomerase and IL-10 to leukemia transformation in the NZB mouse model of human chronic lymphocytic leukemia (CLL). Telomerase levels increased from early to late leukemic stages, likewise IL-10 gene expression levels increased with the leukemic progression. The inverse relationship of telomerase and IL-10 levels to the survival of NZB mice was also established. Our data suggested that telomerase and IL-10 were involved in transformation in the murine model of CLL and the detection of telomerase activities might be of value in the prediction of CLL progression.

Age Factors↗
PubMed2004

VEGF-DT385 toxin conjugate inhibits mammary adenocarcinoma development in a transgenic mouse model of spontaneous tumorigenesis.

Previous experiments have shown that a vascular endothelial growth factor (VEGF)-DT385 toxin conjugate inhibits endothelial cell proliferation, angiogenesis and solid tumor growth in a xenotransplant model system. Here, we report that VEGF-DT385 toxin conjugate effectively inhibits spontaneous tumorigenesis. The C3(1)/SV40 TAg transgenic mouse model of mammary gland carcinogenesis was used to determine the effectiveness of VEGF-DT385 toxin conjugate in delaying the onset of disease and the development of solid tumors. Animals were treated daily with conjugate for a period of 7 days. Therapy was initiated at week 14 of development before any visible adenocarcinomas were evident. Treatment of mice with VEGF-DT385 toxin conjugate significantly delayed the onset of tumorigenesis and inhibited solid tumor growth by more than 92%. Furthermore, conjugate treated animals showed less than twice the number of tumor nodules when compared to control mice. Finally, this vascular targeting agent significantly increased survival time of animals by 5 weeks. VEGF-DT385 toxin conjugate resulted in temporary weight loss and no long-lasting toxicity was seen. More importantly, using this established tumor model, VEGF-DT385 toxin conjugate appeared to be as effective as a similar treatment schedule with recombinant human endostatin. Our results suggest that VEGF-DT385 toxin conjugate is a potent inhibitor of mammary adenocarcinoma growth and might be useful in breast cancer therapy.

Adenocarcinoma↗
PubMed2005

Cross-talk between thyroid hormone receptor and liver X receptor regulatory pathways is revealed in a thyroid hormone resistance mouse model.

Hypercholesterolemia is found in patients with hypothyroidism and resistance to thyroid hormone. In this study, we examined cholesterol metabolism in a thyroid hormone receptor beta (TR-beta) mutant mouse model of resistance to thyroid hormone. Whereas studies of cholesterol metabolism have been reported in TR-beta knock-out mice, generalized expression of a non-ligand binding TR-beta protein in this knock-in model more fully recapitulates the hypothyroid state, because the hypothyroid effect of TRs is mediated by the unliganded receptor. In the hypothyroid state, a high cholesterol diet increased serum cholesterol levels in wild-type animals (WT) but either did not change or reduced levels in mutant (MUT) mice relative to hypothyroidism alone. 7alpha-Hydroxylase (CYP7A1) is the rate-limiting enzyme in cholesterol metabolism and mRNA levels were undetectable in the hypothyroid state in all animals. triiodothyronine replacement restored CYP7A1 mRNA levels in WT mice but had minimal effect in MUT mice. In contrast, a high cholesterol diet markedly induced CYP7A1 levels in MUT but not WT mice in the hypothyroid state. Elevation of CYP7A1 mRNA levels and reduced hepatic cholesterol content in MUT animals are likely because of cross-talk between TR-beta and liver X receptor alpha (LXR-alpha), which both bind to a direct repeat + 4 (DR+4) element in the CYP7A1 promoter. In transfection studies, WT but not MUT TR-beta antagonized induction of this promoter by LXR-alpha. Electromobility shift analysis revealed that LXR/RXR heterodimers bound to the DR+4 element in the presence of MUT but not WT TR-beta. A mechanism for cross-talk, and potential antagonism, between TR-beta and LXR-alpha is proposed.

Animals↗
PubMed2003

Presence of B7-2+ dendritic cells and expression of Th1 cytokines in the early development of sialodacryoadenitis in the IqI/Jic mouse model of primary Sjörgren's syndrome.

Subpopulations of infiltrating lymphocytes, professional antigen-presenting cells (APCs), and Th1/Th2 cytokines that could initiate an autoimmune sialodacryoadenitis were studied in the IQI/Jic mouse model of primary Sjögren's syndrome. Although lymphocytic infiltrations were first seen in submandibular glands (SMGs) of females and in lacrimal glands (LGs) of males at 8 weeks of age, clusters of MHC class II+, CD11c+, B7-2+ dendritic cells (DCs) were already localized in these tissues at 4 weeks. At 8 weeks, the infiltrating lymphocytes consisted of almost equal numbers of B cells and CD4+ T cells. In the inflammatory foci, MHC class II+, CD11c+, B7-2+ DCs formed network-like structures. Duct cells in the lesions showed immunoreactivities for MHC class II and ALCAM (a costimulatory adhesion molecule). IL-12 and IFN-gamma transcripts were detected by RT-PCR in SMGs of females and in LGs of males at 8-12 weeks. These results suggest that the clustered DCs might play an important role in the initiation of the adenitis, and further suggest that the DCs and epithelial cells may participate in the activation of CD4+ T cells. It is also likely that Th1 cytokines mediate the functional interactions between the APCs and CD4+ T cells in the early lesions.

Animals↗
PubMed1997

The role of lipopolysaccharide and Shiga-like toxin in a mouse model of Escherichia coli O157:H7 infection.

The role of lipopolysaccharide (LPS) and Shiga-like toxin (SLT) in the pathogenesis of hemolytic uremic syndrome (HUS) was studied in a mouse model. Mice inoculated intragastrically with Escherichia coli O157:H7 developed gastrointestinal, neurologic, and systemic symptoms, necrotic foci in the colon, glomerular and tubular histopathology, and fragmented erythrocytes. LPS-responder (C3H/HeN) mice developed a combination of neurologic and systemic symptoms, whereas LPS-nonresponder (C3H/HeJ) mice had a biphasic course of disease, first developing systemic symptoms and later severe neurologic symptoms. Mice inoculated with SLT-II-positive strains developed severe neurotoxic symptoms and a higher frequency of systemic symptoms and glomerular pathology compared with SLT-II-negative strains. Anti-SLT-II antibodies protected against these symptoms and pathology. These results demonstrate that this model could be used to study aspects of human HUS and that both LPS and SLT are important for disease development.

Animals↗
PubMed2004

Comparative studies on the efficacy of AmBisome and Fungizone in a mouse model of disseminated aspergillosis.

OBJECTIVES: The efficacy of intravenous injections of a liposomal formulation of amphotericin B (AmBisome) and amphotericin B deoxycholate (Fungizone) was evaluated in immunocompetent and temporarily leucopenic mouse models of disseminated aspergillosis using seven isolates of Aspergillus. METHODS: Mice were infected with the organisms via tail veins. At 4 h after infection, antifungals were administered intravenously. For 30 days the number of mice surviving was recorded. RESULTS: AmBisome at 1 mg/kg or higher significantly prolonged the survival time of mice infected with five out of seven isolates of Aspergillus compared with the control group. There was no difference in in vivo activity between AmBisome and Fungizone at 1 mg/kg in six isolates of Aspergillus. At the maximum tolerated dose of antifungals, however, AmBisome (10 mg/kg) showed greater efficacy than Fungizone (1 mg/kg). CONCLUSIONS: These results suggest that the overall protective activity of AmBisome against disseminated aspergillosis is superior to that of Fungizone.

Amphotericin B↗
PubMed2003

Substrate reduction therapy in mouse models of the glycosphingolipidoses.

Substrate reduction therapy uses small molecules to slow the rate of glycolipid biosynthesis. One of these drugs, N-butyldeoxynojirimycin (NB-DNJ), shows efficacy in mouse models of Tay-Sachs, Sandhoff and Fabry diseases. This offers the prospect that NB-DNJ may be of therapeutic benefit, at least in the juvenile and adult onset variants of these disorders. The infantile onset variants will require an additional enzyme-augmenting modality if the pathology is to be significantly improved. A second drug, N-butyldeoxyglactonojirimycin, looks very promising for treating storage diseases with neurological involvement as high systemic dosing is achievable without any side-effects.

1-Deoxynojirimycin↗