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PubMed2004

A functional analysis of mouse models of cardiac disease through metabolic profiling.

Since the completion of the human and mouse genomes, the focus in mammalian biology has been on assessing gene function. Tools are needed for assessing the phenotypes of the many mouse models that are now being generated, where genes have been "knocked out," "knocked in," or mutated, so that gene expression can be understood in its biological context. Metabolic profiling of cardiac tissue through high resolution NMR spectroscopy in conjunction with multivariate statistics has been used to classify mouse models of cardiac disease. The data sets included metabolic profiles from mouse models of Duchenne muscular dystrophy, two models of cardiac arrhythmia, and one of cardiac hypertrophy. The metabolic profiles demonstrate that the strain background is an important component of the global metabolic phenotype of a mouse, providing insight into how a given gene deletion may result in very different responses in diverse populations. Despite these differences associated with strain, multivariate statistics were capable of separating each mouse model from its control strain, demonstrating that metabolic profiles could be generated for each disease. Thus, this approach is a rapid method of phenotyping mouse models of disease.

Animals↗
PubMed2001

Local gene transfer of tissue inhibitor of metalloproteinase-2 influences vein graft remodeling in a mouse model.

Recently, we established a new mouse model of vein graft arteriosclerosis by grafting vena cava to carotid arteries. In many respects, the morphological features of this murine vascular graft model resemble those of human venous bypass graft disease. Using this model, we studied the effects of local gene transfer of tissue inhibitor of metalloproteinase-2 (TIMP-2) on vein graft remodeling. Mouse isogeneic vessels of the vena caval veins were grafted end to end into carotid arteries, then enveloped with the replication-defective recombinant adenoviruses overexpressing human TIMP-2 (RAdTIMP-2) or beta-galactosidase (RAdLacZ) at 1x10(10) plaque-forming units/mL in a total volume of 50 microL, and incubated at room temperature for 20 minutes. In the untreated group, vessel wall thickening was observed as early as 1 week after surgery and progressed to 4- to 10-fold the original thickness in grafted veins at 4 and 8 weeks, respectively. RAdLacZ vector treatment significantly enhanced neointimal lesions at 8 weeks, which was completely blocked by RAdTIMP-2 gene overexpression. Interestingly, RAdTIMP-2 gene transfer resulted in a reduction in vessel diameter of grafted veins compared with ungrafted veins (819+/-96 versus 624+/-67 microm, respectively; P<0.05). Maximal beta-galactosidase activity was found at 2 weeks and was detectable until 4 weeks after gene transfer. Double immunofluorescence studies demonstrated that cells overexpressing TIMP-2 were mostly localized in the adventitia and were MAC-1-positive monocytes/macrophages but not smooth muscle cells. Furthermore, the activity of matrix metalloproteinases was markedly decreased in the vessel walls treated with RAdTIMP-2 compared with that in the untreated control group and the RAdLacZ-treated group. Thus, this mouse model has been proven to be useful in gene transfer studies. Our findings demonstrate that local TIMP-2 gene transfer significantly reduces vein graft diameter, ie, remodeling to an artery-like vessel via inhibition of matrix metalloproteinase activity.

Adenoviridae↗
PubMed2005

Differential endocrine responses to rosiglitazone therapy in new mouse models of type 2 diabetes.

Polygenic mouse models for obesity-induced type 2 diabetes (T2D) more accurately reflect the most common manifestations of the human disease. Two inbred mouse strains (NON/Lt and NZO/HlLt) separately contributed T2D susceptibility- conferring quantitative trait loci to F1 males. Although chronic administration of rosiglitazone (Rosi) in diet (50 mg/kg) effectively suppressed F1 diabetes, hepatosteatosis was an undesired side effect. Three recombinant congenic strains (designated RCS1, -2, and -10) developed on the NON/Lt background carry variable numbers of these quantitative trait loci that elicit differential weight gain and male glucose intolerance syndromes of variable severity. We previously showed that RCS1 and -2 mice responded to chronic Rosi therapy without severe steatosis, whereas RCS10 males were moderately sensitive. In contrast, another recombinant congenic strain, RCS8, responded to Rosi therapy with the extreme hepatosteatosis observed in the F1. Longitudinal changes in multiple plasma analytes, including insulin, the adipokines leptin, resistin, and adiponectin, and plasminogen activator inhibitor-1 (PAI-1) allowed profiling of the differential Rosi responses in steatosis-exacerbated F1 and RCS8 males vs. the resistant RCS1 and RCS2 or moderately sensitive RCS10. Of these biomarkers, PAI-1 most effectively predicted adverse drug responses. Unexpectedly, mean resistin concentrations were higher in Rosi-treated RCS8 and RCS10. In summary, longitudinal profiling of multiple plasma analytes identified PAI-1 as a useful biomarker to monitor for differential pharmacogenetic responses to Rosi in these new mouse models of T2D.

Adiponectin↗
PubMedDate not supplied

A mouse model of influenza protection.

A mouse model has been developed in order to examine the parts played by humoral and cellular mechanisms in influenza immunity. Protection is assessed in terms of the amount of virus detectable in the lungs within 48 h of challenge. This system has two major advantages over the more common mouse lethality models. It is no longer necessary to use a mouse-lethal strain of virus; and protection is measured within days rather than weeks of challenge. Thus it is possible to determine the ability of the immune system to limit infection at an early stage, as distinct from curing a pre-existing infection and so preventing death. Transfer of spleen cells from an immune donor to a normal recipient will significantly reduce the amount of virus found in the lungs 24 h after challenge. The transferred cells are, however, capable of producing significant serum levels of anti-influenza antibody. Administration of serum from immune mice to normal recipients also results in a significant degree of protection within 24 h of challenge. These results give additional evidence that in the mouse significant protection is provided by serum antibody very soon after infection, but do not exclude the possibility that a part may be played by other mechanisms.

Animals↗
PubMed2002

Environmental carcinogens and p53 tumor-suppressor gene interactions in a transgenic mouse model for mammary carcinogenesis.

Mouse mammary tumorigenesis is greatly influenced by a variety of exogenous agents, such as MMTV, chemical carcinogens (i.e., polycyclic aromatic hydrocarbons), and radiation, as well as by endogenous/physiological factors, such as steroid hormones, tumor-suppressor genes (i.e., Brca1/2, p53), and gene products of modifier genes. In the mouse model, the most frequently used chemical carcinogen has been 7,12-dimethylbenz[a]anthracene (DMBA), which activates the Ha-ras gene but does not alter the p53 tumor-suppressor gene. However, on an existing background of p53 gene alteration, low doses of DMBA are strongly cocarcinogenic. Using a transgenic model system, in which the p53 gene was deleted in the mammary gland, we examined the carcinogenic effects of a variety of external agents and internal factors given at either low doses or physiological doses. These agents/factors included DMBA, gamma-radiation, Brca2 heterozygosity, and steroid hormones. All agents/factors increased the tumorigenic response of the p53 null mammary cells, even under conditions where no tumorigenic response was observed in the p53 wildtype mammary cell. The strongest cocarcinogenic effect was observed with the steroid hormone progesterone. The majority of tumors were highly aneuploid and composed of nuclear igh-grade cells. The mechanism for the aneuploidy and secondary events associated with high tumorigenicity were examined using array technology. These results demonstrate that, on a background of underlying genetic instability, very low doses of environmental mutagens and mitogens can produce strong cocarcinogenic effects.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1995

Inverse expressions of the N-myc oncogene and beta 1 integrin in human neuroblastoma: relationships to disease progression in a nude mouse model system.

A nude mouse model for human neuroblastoma has been developed to examine possible relationships between amplification/over-expression of the N-myc oncogene and altered regulation of expression of specific integrin subunits during tumor progression. Subcutaneous (ectopic) or intra-adrenal (orthotopic) injection of the neuroblastoma cell lines SK-N-SH or IMR-32 has generated a number of derivative tumor cell lines. Tumor cell lines derived from SK-N-SH cells (which do not express N-myc) or IMR-32 cells (which over-express N-myc) produce tumors at higher rates when re-injected into the subcutaneous space of nude mice. Moreover, cell lines derived from tumors initiated by IMR-32 cells exhibit shorter latent periods than do IMR-32 cells direct from tissue culture. With regard to integrin subunit expression, SK-N-SH and related cell lines express high levels of beta 1 integrin, which is associated with the alpha 2 and alpha 3 integrin subunits (predominantly alpha 3). IMR-32 cells display reduced beta 1 expression, and that which is produced is not associated with common alpha subunits. LaN1 cells, which express N-myc at even higher levels than do IMR-32 cells, express even less beta 1. Interestingly, the tumor-derived cell lines (especially those from tumors initiated in adrenal glands) also exhibit reduced integrin expression compared with the parental cell lines; this reduction is associated with the enhanced tumor take rate observed when the cells are re-injected into nude mice. Our results raise the possibility of a relationship between over-expression of N-myc and down-regulation of beta 1 integrin expression (possibly some alpha subunits also). In addition, the data suggest that human neuroblastoma-derived cell lines which exhibit reduced integrin expression display more aggressive tumor growth in nude mice.

Animals↗
PubMed1975

Experimental studies of the pathogenesis of infections due to Pseudomonas aeruginosa: description of a burned mouse model.

An experimental burned mouse model is described that is clinically relevant to burn wound sepsis caused by Pseudomonas aeruginosa. Mice subjected to a nonlethal burn by flame were challenged with P. aeruginosa. The LD50 after subcutaneous injection in the skin of the burn up to 24 hr after the burn was smaller than 10 organisms vs. 10-6 organisms in normal animals. By three days after the burn, the value returned to and exceeded that of normal animals. This dramatic change in the LD50 after the burn was not seen when mice were challenged with other organisms. Challenge with P. aeruginosa by different routes immediately after burning showed less dramatic decreases in the LD50. Enumeration of infecting organisms in the skin of the burn and in major organs suggests the possibility of a toxic event.

Animals↗
PubMed2006

Anomaly of anatomical origin of soleus muscle: a mouse model.

In the laboratory mouse, the soleus muscle arises at the head of the fibula and inserts via the Achilles tendon on the tuber calcanei together with the gastrocnemius muscle. During routine dissection of mice from the BXD recombinant inbred (RI) strains, we found that the soleus often originated from the lateral epicondyle of the femur instead of the head of the fibula. This soleus femoral attachment anomaly (SFAA) changes the soleus from being a single-joint to a two-joint muscle. The incidence of SFAA was 45% in the BXD38 RI strain. Bilateral inspection indicated that SFAA may be present unilaterally or bilaterally within an individual mouse. We explored the effect of SFAA on muscle weight in mice with unilateral expression. The weight of SFAA soleii was significantly less (P < 0.01) than that of the soleii with normal attachment by 6% (females) and 14% (males). Similar anatomical anomalies of the soleus muscle have been noted in humans. The mouse model will provide the means to explore the physiological consequences and genetic basis for such anomalies.

Animals↗
PubMed1983

Passive protection against Pseudomonas aeruginosa infection in an experimental leukopenic mouse model.

An experimental leukopenic mouse model was used to evaluate the protective capacities of immunoglobulin G (IgG) fractions directed against toxin A (AT-IgG), elastase (AE-IgG), and lipopolysaccharide (ALPS-IgG) against fatal Pseudomonas aeruginosa infection. Statistically significant protection, as measured by long-term survival, was observed only when mice were treated with serotype-specific ALPS-IgG. The mean lethal dose for P. aeruginosa could be increased by as much as 6,600-fold for mice given ALPS-IgG as compared to mice which received only normal rabbit IgG. ALPS-IgG afforded high levels of protection, even when administered up to 6 h postchallenge. Experiments designed to monitor the growth and spread of a locally administered challenge showed that ALPS-IgG prevented bacteremia and organ colonization, which were pronounced in control animals. The effectiveness of combined antibiotic and immune therapy was tested. Gentamicin alone or in combination with AT-IgG or AE-IgG provided no detectable protection. However, its use with ALPS-IgG afforded substantially higher levels of protection than ALPS-IgG alone.

Animals↗
PubMed2004

Cre/loxP system for generating tissue-specific knockout mouse models.

Alteration of the mouse genome by conventional transgenic and gene-targeted approaches has greatly facilitated studies of gene function. However, a gene alteration expressed in the germ line may cause an embryonic lethal phenotype resulting in no viable mouse to study gene function. Similarly, a gene alteration may exert its effect in multiple different cell and tissue types, creating a complex phenotype in which it is difficult to distinguish direct function in a particular tissue from secondary effects resulting from altered gene function in other tissues. Therefore, methods have been developed to control conditions such as the timing, cell-type, and tissue specificity of gene activation or repression. This brief review provides an overview of the Cre/LoxP system for generating tissue-specific knockout mouse models.

Animals↗
PubMed1998

A mouse model of graded contusive spinal cord injury.

A mouse model of spinal cord injury (SCI) could further increase our basic understanding of the mechanisms involved in injury and recovery by taking advantage of naturally-occurring and genetically engineered mutations available in mice. We have, therefore, investigated whether methods used to produce and evaluate graded experimental contusive SCI in the rat could be modified to produce a mouse model of traumatic SCI. C57BL6 mice were anesthetized with 2,2,2-tribromoethanol and a restricted laminectomy performed at the T8 vertebral level. The spinal column was stabilized and a weight drop technique used to produce contusive injury. Experimental groups were distinguished by the amount of weight or the height from which the weight was dropped onto an impounder resting on the dura (1 g x 2.5 cm, 2 g x 2.5 cm, 3 g x 2.5 cm, and 3 g x 5.0 cm). Functional deficits over time were examined up to 28 days after SCI by testing hindlimb reflex responses and coordinated motor function. Chronic lesion histopathology was evaluated by light microscopy and analyzed with morphometric techniques. All groups demonstrated profound functional deficits after injury followed by gradual recovery. Recovery correlated with the weight dropped and percent of white matter spared that was 41.3+/-6.0% (mean +/- SEM) in the 2 g x 2.5 cm group and 24.3+/-5.0% in the 3 g x 2.5 cm group. A replicate experiment confirmed reproducibility of the injury. This new mouse model of contusive SCI could pave the way for in vivo studies of the effect of genetic modifications produced by specific mutations on injury and recovery processes after spinal cord trauma.

Animals↗
PubMed1996

A mouse model of familial hypertrophic cardiomyopathy.

A mouse model of familial hypertrophic cardiomyopathy (FHC) was generated by the introduction of an Arg 403 --> Gln mutation into the alpha cardiac myosin heavy chain (MHC) gene. Homozygous alpha MHC 403/403 mice died 7 days after birth, and sedentary heterozygous alpha MHC 403/+ mice survived for 1 year. Cardiac histopathology and dysfunction in the alpha MHC 403/+ mice resembled human FHC. Cardiac dysfunction preceded histopathologic changes, and myocyte disarray, hypertrophy, and fibrosis increased with age. Young male alpha MHC 403/+ mice showed more evidence of disease than did their female counterparts. Preliminary results suggested that exercise capacity may have been compromised in the alpha MHC 403/+ mice. This mouse model may help to define the natural history of FHC.

Animals↗
PubMed2006

Mouse models of 22q11 deletion syndrome.

22q11 deletion syndrome (22q11DS) is caused by an interstitial chromosomal microdeletion that encompasses about 40 genes. It is the most common of the microdeletion syndromes. The clinical phenotype, which is complex and variable, includes specific congenital defects of the cardiovascular system, craniofacies, and immune system. In early childhood, patients manifest cognitive impairment, behavioral disorders, and delays in motor development and language acquisition. Adult patients have a high risk for developing serious psychiatric disorders, especially schizophrenia, schizoaffective disorder, and bipolar disorder. The great majority of patients have an identical or near identical chromosomal deletion, and genotype-phenotype correlations have not been established. Indeed, little progress was made toward resolving the complex clinical phenotype until the deletion was successfully modeled in the mouse. In recent years, through a variety of mouse mutants that carry multigene and single gene mutations, we have learned that mutation in a single gene, Tbx1, is responsible for most of the congenital defects seen in the mouse models and in patients. We now face a greater challenge as we attempt to use the mouse to address the pathogenesis of the behavioral and psychiatric disorders associated with 22q11DS. Significant progress has already been made, and recent studies in the mouse suggest that several genes from the deleted region affect behavior and might contribute to disease burden in patients.

Animals↗
PubMed2006

Intraneuronal amyloid beta and reduced brain volume in a novel APP T714I mouse model for Alzheimer's disease.

Transgenic mouse models of Alzheimer's disease (AD) expressing high levels of amyloid precursor protein (APP) with familial AD (FAD) mutations have proven to be extremely useful in understanding pathogenic processes of AD especially those that involve amyloidogenesis. We earlier described Austrian APP T714I pathology that leads to one of the earliest AD age-at-onsets with abundant intracellular and extracellular amyloid deposits in brain. The latter strikingly was non-fibrillar diffuse amyloid, composed of N-truncated A beta 42 in absence of A beta 40. In vitro, this mutation leads to one of the highest A beta 42/A beta 40 ratios among all FAD mutations. We generated an APP T714I transgenic mouse model that despite having 10 times lower transgene than endogenous murine APP deposited intraneuronal A beta in brain by 6 months of age. Accumulations increased with age, and this was paralleled by decreased brain sizes on volumetric MRI, compared to age-matched and similar transgene-expressing APP wild-type mice, although, with these levels of transgenic expression we did not detect neuronal loss or significant memory impairment. Immunohistochemical studies revealed that the majority of the intraneuronal A beta deposits colocalized with late endosomal markers, although some A beta inclusions were also positive for lysosomal and Golgi markers. These data support earlier observations of A beta accumulation in the endosomal-lysosomal pathway and the hypothesis that intraneuronal accumulation of A beta could be an important factor in the AD pathogenesis.

Alzheimer Disease↗
PubMed1989

Significance of toxin-coregulated pili as protective antigens of Vibrio cholerae in the infant mouse model.

The infant mouse cholera model has been used to evaluate the relative importance of toxin-coregulated pili (TCP) as protective antigens of Vibrio cholerae 01. Electron microscopic and immunoblotting analyses revealed that, under the cultural conditions examined, TCP were only expressed by strains of classical biotype. Antibodies to TCP were sufficient to confer protection against two such strains, and were more efficient if the challenge vibrios were cultured for TCP expression. In contrast, such antibodies did not protect mice against challenge with any of four strains of El Tor biotype. Since two of the latter have previously been shown to possess non-lipopolysaccharide protective antigens, these results suggest that TCP are not the only such antigen in this model.

Animals↗
PubMed1985

Optimal timing of adjuvant chemotherapy in mouse models.

In three mouse tumor models the effect of timing of adjuvant chemotherapy with a single dose of cyclophosphamide was studied. In one tumor, preoperative adjuvant therapy was better than postoperative therapy. In a second tumor, the reverse was the case, and in the third model there was no difference resulting from variation in the timing of cytostatic drug therapy. Obviously, the concept that a standard drug dose always gives a constant relative cell kill is not always a valid simplification of dose-effect relationships in chemotherapy.

Animals↗
PubMed2005

Mouse models of colorectal cancer and liver metastases.

Colorectal cancer (CRC) is one of the most common malignancies in the western world. Its high mortality rates are particularly related to the occurrence of liver metastases. Many mouse models have been developed to evaluate the various features of CRC in human. Since none of the existing mouse models mimics all the characteristics of human CRC, it is of crucial importance that the optimal model is chosen for each experiment to resolve a specific experimental question. Currently used mouse models for CRC include chemically induced CRC models, genetically engineered mouse models and models in which colon tumors are implanted in recipient mice. Recently, conditional mouse models have been created in which a gene of interest can be (in)activated in a time- and tissue-specific manner. All models have their advantages and limitations. This review highlights the most commonly used mouse models for CRC and its liver metastases, their usefulness and shortcomings, as well as recent improvements, particularly regarding intravital (tumor) imaging.

Animals↗
PubMed2001

Peritoneal mesothelial hypoxia during pneumoperitoneum is a cofactor in adhesion formation in a laparoscopic mouse model.

OBJECTIVE: To develop a laparoscopic mouse model to evaluate the hypothesis that mesothelial hypoxia during pneumoperitoneum is a cofactor in adhesion formation. DESIGN: Prospective randomized trials. SETTING: Academic research center. ANIMAL(S): One hundred thirty female Naval Medical Research Institute (NMRI) mice. INTERVENTION(S): Adhesions were induced by opposing monopolar lesions in uterine horns and pelvic side walls during laparoscopy and evaluated after 7 or 28 days under microscopic vision during laparotomy. The following pneumoperitoneum variables were assessed: duration (10 or 60 minutes), insufflation pressure (5 or 15 cm of water), insufflation gas (CO(2) or helium), and addition of oxygen (0-12%). MAIN OUTCOME MEASURE(S): Adhesions were scored quantitatively and qualitatively for extent, type, and tenacity. RESULT(S): Scoring of adhesions 7 or 28 days after laparoscopic surgery was comparable. Adhesions increased with duration of pneumoperitoneum and with insufflation pressure and decreased with the addition of oxygen. Half-maximal reduction of adhesions was obtained at 1.5% oxygen, whereas a maximal reduction required only 2%-3%. The effect of CO(2) and helium was similar. CONCLUSION(S): These data demonstrate the feasibility of the intubated laparoscopic mouse model and confirm previous observations in rabbits, indicating that mesothelial hypoxia plays a key role in adhesion formation.

Animals↗