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At least 55 records · Page 3Linked to original sources
PubMed1991

Efficacy of a Proteus mirabilis outer membrane protein vaccine in preventing experimental Proteus pyelonephritis in a BALB/c mouse model.

A BALB/c mouse model of nonobstructive, ascending Proteus mirabilis pyelonephritis was characterized bacteriologically, histologically, and serologically from 3 to 28 days. Intravesicular administration of 2 X 10(8) P. mirabilis K7 resulted in the septic death of 9 (16%) of 57 mice by day 15. Among the survivors, K7 colonized the kidneys in great numbers until day 21. Histological examination of the kidneys revealed acute inflammation which was characterized by neutrophil infiltration by day 3, renal necrosis by day 7, and fibroblastic infiltration by day 14 which persisted at least until day 28. The immunoglobulin G response to the outer membrane proteins (OMP) was assessed by enzyme-linked immunosorbent assay and Western blotting (immunoblotting). Anti-OMP immunoglobulin G antibodies were detected as early as day 7, and the reciprocals of their titers rose progressively up to day 28 (i.e., greater than or equal to 500). This model was also used to assess the efficacy of OMP and lipopolysaccharide (LPS) immunization in preventing renal infection. K7 OMP or LPS (100 micrograms) preparations were administered intramuscularly in Freund's complete adjuvant. After 2 weeks, mice were intravesicularly challenged with 2 X 10(8) bacteria of the homologous K7 strain or one of four heterologous strains. Compared with the saline-immunized control group and K7 LPS-immunized mice, K7 OMP recipients were protected from death when challenged by homologous or heterologous strains. In addition, K7 OMP recipients were protected (P less than 0.003) from subsequent renal infection when challenged by the K7 strain and had more rapid bacterial renal clearance when challenged by three of four heterologous strains. OMP recipients produced antibodies which bound major OMP moieties (viz., 36- to 39-kDa cell wall constituents) as assessed by Western blotting. These results support the concept that immunization with selected bacterial protein surface coat constituents can prevent uromucosal infection by interfering with colonization or renal injury.

Animals↗
PubMed1999

The role of p53 in tumour suppression: lessons from mouse models.

The use of mouse models has greatly contributed to our understanding of the role of p53 in tumour suppression. Mice homozygous for a deletion in the p53 gene develop tumours at high frequency, providing essential evidence for the importance of p53 as a tumour suppressor. Additionally, crossing these knockout mice or transgenic expression p53 dominant negative alleles with other tumour-prone mouse strains has allowed the effect of p53 loss on tumour development to be examined further. In a variety of mouse models, absence of p53 facilitates tumorigenesis, thus providing a means to study how the lack of p53 enhances tumour development and to define genetic pathways of p53 action. Depending on the particular model system, loss of p53 either results in deregulated cell-cycle entry or aberrant apoptosis (programmed cell death), confirming results found in cell culture systems and providing insight into in vitro function of p53. Finally, as p53 null mice rapidly develop tumours, they are useful for evaluating agents for either chemopreventative or therapeutic activities.

Animals↗
PubMed1990

Pathogenesis of Campylobacter fetus infections. Role of surface array proteins in virulence in a mouse model.

We developed a mouse model to compare the virulence of Campylobacter fetus strains with (S-plus) and without (S-minus) surface array protein (S-protein) capsules. In adult HA/ICR mice pretreated with ferric chloride, the LD50 for S-plus strain 84-32 was 43.3 times lower than its spontaneous S-minus mutant 84-54. Seven strains of inbred mice were no more susceptible than the outbred strain. In contrast to the findings with Salmonella typhimurium by others, 3 X 10(7) CFU of strain 84-32 caused 90% mortality in C3H/HeN (LPSn) mice and 40% mortality in C3H/HeJ (LPSd) mice. High-grade bacteremia in HA/ICR mice occurred after oral challenge with S-plus C. fetus strains and continued for at least 2 d, but was not present in any mice challenged with S-minus strains. Bacteremia at 30 min after challenge was 51.6-fold lower in mice pretreated with 10 microliters of rabbit antiserum to purified S-protein than after pretreatment with normal rabbit serum. Challenge of mice with a mixture of S-minus strain 84-54 and free S-proteins at a concentration 31.1-fold higher than found in wild-type strain 84-32 caused 30% mortality, compared with 0% with strain 84-54 or S-protein alone. These findings in a mouse model point toward the central role of the S-protein in the pathogenesis of C. fetus infection. The S-protein is not toxic per se, but enhances virulence when present on the bacterial cell surface as a capsule.

Animals↗
PubMed1988

Neonatal hepatitis induced by alpha 1-antitrypsin: a transgenic mouse model.

Transgenic mouse lineages were established that carry the normal (M) or mutant (Z) alleles of the human alpha 1-antitrypsin (alpha 1-Pi) gene. All of the alpha 1-Pi transgenic mice expressed the human protein in the liver, cartilage, gut, kidneys, lymphoid macrophages, and thymus. The human M-allele protein was secreted normally into the serum. However, the human Z-allele protein accumulated in several cell types, but particularly in hepatocytes, and was found in serum in tenfold lower concentrations than the M-allele protein. Mice in one lineage carrying the mutant Z allele expressed high levels of human alpha 1-Pi RNA and displayed significant runting (50% of normal weight) in the neonatal period. This lineage was found to have alpha 1-Pi-induced liver pathology in the neonatal period, concomitant with the accumulation of human Z protein in diastase-resistant cytoplasmic globules that could be revealed in the Periodic acid-Schiff reaction (PAS). The phenotype of mice in the strain expressing high levels of the Z allele is remarkably similar to human neonatal hepatitis, and this strain may prove to be a useful animal model for studying this disease.

Alleles↗
PubMed2003

Central nervous system inflammation is a hallmark of pathogenesis in mouse models of GM1 and GM2 gangliosidosis.

Mouse models of the GM2 gangliosidoses [Tay-Sachs, late onset Tay-Sachs (LOTS), Sandhoff] and GM1 gangliosidosis have been studied to determine whether there is a common neuro-inflammatory component to these disorders. During the disease course, we have: (i) examined the expression of a number of inflammatory markers in the CNS, including MHC class II, CD68, CD11b (CR3), 7/4, F4/80, nitrotyrosine, CD4 and CD8; (ii) profiled cytokine production [tumour necrosis factor alpha (TNF alpha), transforming growth factor (TGF beta 1) and interleukin 1 beta (IL1 beta)]; and (iii) studied blood-brain barrier (BBB) integrity. The kinetics of apoptosis and the expression of Fas and TNF-R1 were also assessed. In all symptomatic mouse models, a progressive increase in local microglial activation/expansion and infiltration of inflammatory cells was noted. Altered BBB permeability was evident in Sandhoff and GM1 mice, but absent in LOTS mice. Progressive CNS inflammation coincided with the onset of clinical signs in these mouse models. Substrate reduction therapy in the Sandhoff mouse model slowed the rate of accumulation of glycosphingolipids in the CNS, thus delaying the onset of the inflammatory process and disease pathogenesis. These data suggest that inflammation may play an important role in the pathogenesis of the gangliosidoses.

1-Deoxynojirimycin↗
PubMedDate not supplied

Preliminary evidence of phenytoin-induced alterations in embryonic gene expression in a mouse model.

SWV mouse embryos collected on gestational days (GD) 9:12 and 10:00 following chronic in utero exposure to teratogenic concentrations of phenytoin were utilized for in situ transcription studies of gene expression. The substrate cDNA obtained from the frozen embryo sections was amplified into radiolabelled antisense RNA (RT/aRNA) and used as a probe to screen a panel of 20 cDNA clones representing genes that are important regulators of craniofacial and neural development. The magnitude of alteration in gene expression following phenytoin treatment was determined densitometrically by changes in the hybridization intensity of the aRNA probes to the cDNA clones immobilized to the slot blots. We found that both Wnt-1 and the calcium channel gene were developmentally regulated, as their level of expression decreased significantly between the two collection times. Phenytoin treatment produced a significant downregulation in the level of expression for 25% of the genes examined in the GD 9:12 embryos, including the growth factors TGF-beta and NT3, the proto-oncogene Wnt-1, the nicotinic receptor, and the voltage sensitive calcium channel gene. Additional changes in the coordinate expression of several of the growth and transcription factors were observed at both gestational timepoints. The application of RT/aRNA technology has extended our appreciation of the normal patterns of gene expression during craniofacial and neural development, and provided the first demonstration of multiple coordinate changes in transcription patterns following teratogenic insult.

Analysis of Variance↗
PubMed1992

Profiles of interaction of R(+)/S(-)-zacopride and anxiolytic agents in a mouse model.

The mouse black and white test box was used to measure changes in behaviour in an aversive situation where the administration of R(+)-zacopride (but not S(-)-zacopride) alone decreased aversive responding to the white area. A similar anxiolytic profile of action was observed using parachlorophenylalanine (PCPA), whose effects were antagonised by a co-treatment with R(+)-zacopride and reversed by S(-)-zacopride to an exacerbation of the aversive response. An anxiolytic profile of action was also observed using ondansetron, granisetron, chlordiazepoxide, diazepam, ritanserin, 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), E4424 (2-[4-[4-(4-chloro-l-pyrazoyl)butyl]-l-piperazinyl]-pyrimidine), umepsirone, DuP753 (2-n-butyl-4-chloro-5-hydroxy-methyl-1-[2(1H-tetrazol-5-yl) biphenyl-4-yl)methyl)]-imidazole), SQ29,852 ((S)-1-[6-amino-2[hydroxy)(4-phenyl-butyl)phosphinyl]-oxy)-1- nexy]-2-proline), devazepide and guanfacine, and this was retained following co-treatment with PCPA. The anxiolytic profile of action of PCPA was also retained following co-treatment with renzapride which when administered alone failed to modify behaviour. However, the ability of chlordiazepoxide, diazepam, ondansetron and E4424 (but not devazepide, DuP753 or SQ29,852) to reduce aversive responding was inhibited by co-treatment with R(+) and/or S(-)-zacopride. It is concluded that the reduction in aversive responding caused by pharmacological manipulation at the benzodiazepine, 5-HT receptor subtypes 5-HT1A, 5-HT1C/5-HT2 and 5-HT3 (but not at the cholecystokin CCKA or angiotensin receptors or inhibition of angiotensin converting enzyme) can be inhibited by R(+) and S(-)-zacopride. The data is discussed in terms of zacopride having an agonist or partial agonist effect at the 5-HT3 receptor.

Animals↗
PubMedDate not supplied

Genetic mouse models of extended lifespan.

Since 1996, seven genetic mouse models have been reported to show increased lifespan: Ames and Snell dwarf mice, the 'little mouse' (Ghrhr(lit/lit)), mice null for either growth hormone receptor/binding protein (GHR/BP(-/-)) or p66(shc) (p66(shc-/-)), mice heterozygous for the IGF-I receptor (Igf1r(+/-)), and fat-specific insulin receptor knockout mice. In this article, we describe and evaluate these mouse models with respect to their relevance for aging studies. While these seven genetic models all show a significant increase in lifespan, issues of sample size and animal husbandry procedures require further evaluation before firm conclusions can be drawn on the reproducibility of life extension in most of these mouse models. Because data on the age-related pathology and physiological functions are lacking for all of the models, except the dwarf mice, it is too early to conclude that aging is retarded in these mouse models. However, these mouse models are already providing new information about the mechanism underlying mammalian aging.

Aging↗
PubMed1989

Salmonella typhimurium virulence in a burned-mouse model.

Various features of salmonellosis were examined in a burned-mouse model. In this model, which uses an outbred mouse strain, a challenge dose of ca. 100 CFU with any of several strains of Salmonella typhimurium caused a fatal infection. A variety of mutated strains attenuated for virulence in Salmonella-susceptible parenterally infected mice were also attenuated in the burned-mouse model. When administered as live vaccines injected intraperitoneally the same attenuated strains provided between slight and complete protection against subsequent lethal challenge subcutaneously at the site of a burn. The correspondence of results obtained in the burned-mouse model with those seen in other mouse models coupled with the unique advantages of the burned-mouse model argue for the usefulness of the model in studies of salmonellosis and in testing of strains constructed for use as live vaccines.

Animals↗
PubMed1995

Efficacy of AZT therapy in reducing p24 antigen burden in a modified SCID mouse model of HIV infection.

A modified severe combined immunodeficient (SCID) mouse model of HIV infection which utilized multiple reconstitutions with human lymphocytes and a large inoculum of HIV was investigated. This mouse model yielded splenic HIV p24 antigen concentrations detectable by standard clinical means. The concentration of p24 exceeded 600 pg/g of spleen through 4 weeks postinfection. A 1-week course of AZT therapy initiated after infection produced a dose responsive reduction in p24 antigen burden. Up to a 95% reduction in p24 antigen burden was observed following AZT therapy at 50 mg/kg/day, while AZT therapy at 5 and 0.5 mg/kg/day produced 52 and 18% reductions. In vitro and pharmacokinetic evaluations correlated potency and tissue concentrations of AZT with treatment efficacy. Active HIV replication in the SCID mice was suggested by both the recovery of viable virus from SCID spleens, and by the efficacy of a brief course of AZT therapy. This SCID mouse model of HIV infection was more quantitative than previous mouse models that utilize PCR-based techniques for detection of HIV. The high HIV burden in this SCID mouse model allowed reductions in p24 concentration to be monitored in response to AZT therapy. A dose response to AZT therapy was demonstrated, even when the first dose was administered after infection. This result suggests greater sensitivity than in previous models in which pretreatment with AZT was required to produce a protective response. This SCID mouse model may be useful for determining efficacy of experimental HIV therapeutics prior to clinical use. An effective animal model could result in a reduction in cost and more rapid development of effective HIV therapeutics.

Animals↗
PubMed2004

Mouse models of abdominal aortic aneurysms.

Many mouse models of abdominal aortic aneurysms have been developed that use a diverse array of methods for producing the disease, including genetic manipulation and chemical induction. These models could provide insight into potential mechanisms in the development of this disease. Although experimental studies on abdominal aortic aneurysms (AAAs) have used a variety of mammalian and avian approaches, there is an increasing reliance on the use of mice. The models recapitulate some facets of the human disease including medial degeneration, inflammation, thrombus formation, and rupture. Most of the mouse models of AAA are evoked either by genetically defined approaches or by chemical means. The genetic approaches are spontaneous and engineered mutations. These include defects in extracellular matrix maturation, increased degradation of elastin and collagen, aberrant cholesterol homeostasis, and enhanced production of angiotensin peptides. The chemical approaches include the intraluminal infusion of elastase, periaortic incubations of calcium chloride, and subcutaneous infusion of AngII. A common feature of these models is the reduction of AAA incidence and severity by the prophylactic administration of matrix metalloproteinase (MMP) inhibitors or genetically engineered deficiencies of specific members of this proteolytic protein family. The validation of mouse models of AAAs will provide insight into the mechanisms of progression of the human disease.

Angiotensin II↗
PubMedDate not supplied

Tumor spectrum in the p53 heterozygous zeta globin-promoted Tg.AC (v-Ha-ras) bitransgenic mouse model.

The use of a bitransgenic mouse model for cancer is an effective approach for studying the impact of specific carcinogens and the occurrence of tissue-specific lesions. We studied the novel p53 heterozygous zeta globin-promoted Tg.AC (v-Ha-ras) mouse model because these mice contain a carcinogen-inducible ras oncogene and one functional p53 tumor suppressor allele, both of which occur frequently in human cancers. Our aim was to characterize the short-term control and chemically induced tumor spectrum in this novel model. Mice were placed on basal semipurified diet containing 20% soy protein for 2 weeks prior to random allocation to groups. Subsequently, 15 male and 15 female mice were administered corn oil vehicle alone or containing benzo(a)pyrene (20 mg/kg body weight) via oral gavage 2 times per week for 10 weeks with subsequent observation for 18 weeks. Mice exhibited lesions characteristic of FVB/N, p53 heterozygous and Tg.AC mouse models. However, an array of unique, novel lesions were observed including uterine leiomyosarcomas, mammary gland carcinomas, mammary squamous cell carcinomas, and parotid salivary gland carcinomas suggesting tissue-specific interactions of the 2 genotypes. Thus, this bitransgenic model may provide further insight into the mechanistic interaction of 2 genes commonly mutated in neoplasia.

Alleles↗
PubMed2002

Mouse models for neurological disease.

The mouse has many advantages over human beings for the study of genetics, including the unique property that genetic manipulation can be routinely carried out in the mouse genome. Most importantly, mice and human beings share the same mammalian genes, have many similar biochemical pathways, and have the same diseases. In the minority of cases where these features do not apply, we can still often gain new insights into mouse and human biology. In addition to existing mouse models, several major programmes have been set up to generate new mouse models of disease. Alongside these efforts are new initiatives for the clinical, behavioural, and physiological testing of mice. Molecular genetics has had a major influence on our understanding of the causes of neurological disorders in human beings, and much of this has come from work in mice.

Animals↗
PubMed2003

Tumorigenic potential of carbaryl in the heterozygous p53 knockout mouse model.

The heterozygous p53 knockout mouse model was used to assess whether vascular tumors noted in a 2-year carcinogenicity study in CD-1 mice with carbaryl were induced through a genotoxic mechanism. This knockout mouse model was selected for carbaryl because of the high sensitivity of this model to genotoxic events and its low spontaneous incidence of tumors until 9-12 months of age. Carbaryl was administered continuously via the diet to groups of 20 male heterozygous p53 knockout mice at concentrations of 0, 10, 30, 100, 300, 1000 and 4000 ppm for 180 days. Histopathological examinations revealed no evidence of carbaryl-induced neoplasms of any type. In particular, no neoplastic or preneoplastic changes were noted in the vascular tissue of any of the organs examined. Only neoplasms, recognized as those that occur spontaneously in untreated mice of this strain, were sporadically observed in a few animals from the intermediate dose groups with no evidence of a dose- or treatment-related effect. Therefore, under the conditions of this study, the no-observed-effect level (NOEL) of carbaryl for neoplastic changes in male mice was 4000 ppm (around 716 mg/kg body weight/day). We conclude: (1) carbaryl does not appear to be a genotoxic carcinogen at least in male mice; (2) if the vascular tumors observed in the CD-1 mice are treatment-related, they could have been induced by a non-genotoxic mechanism; (3) the response in transgenic animals may provide useful complementary results to better assess carbaryl's potential genotoxic hazard to humans.

Animals↗
PubMed1988

Characterization of a mouse model of chronic uremia.

A mouse model of renal failure, which is induced by the sequential electrocoagulation of the right renal cortex and left nephrectomy, was examined for the capacity to reproduce the characteristics of chronic uremia. Assessment was conducted six weeks after the second surgical procedure in 13 week old female C57BL/6 inbred mice with renal failure and in normal and sham-operated controls. The surgery, which was well tolerated, was free of local and systemic signs of inflammation or infection. Growth was significantly delayed in all animals post surgery however renal failure mice presented the most severe growth retardation. Biochemical analysis of plasma revealed multiple abnormalities with commensurate elevations of urea and creatinine. In addition to the expected hyperphosphatemia, hyperkalemia and acidosis, a significant increase in cholesterol was present. Furthermore, in contrast to controls, renal failure mice produced large volumes of urine which contained significant levels of protein. Renal failure mice presented profound hematological changes in the red cell series in which anemia was evident. Changes in plasma biochemistry and in bone histology revealed the presence of severe secondary hyperparathyroidism. It was therefore concluded that the described mouse model of chronic renal failure presented characteristics consistent with those observed clinically in end-stage renal disease.

Animals↗
PubMed2001

Mouse model of Parkinsonism: a comparison between subacute MPTP and chronic MPTP/probenecid treatment.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is widely used to induce an animal model of Parkinsonism. The conventional mouse model, which usually involves acute or subacute injections of MPTP, results in a significant but reversible loss of dopaminergic functions. We have developed an alternative mouse model, in which co-administration of MPTP with probenecid results in the chronic loss of striatal dopamine for at least 6 months after cessation of treatment. In the present study, we compare the neurochemical, morphological and behavioral changes that occur in this alternative, chronic model with those in the conventional, subacute model. In the chronic model, we demonstrate an almost 80% loss of striatal dopamine and dopamine uptake 6 months after withdrawal from treatment. The neurochemical signs match unbiased stereological measures that demonstrate gradual loss of substantia nigra neurons. Rotarod performance further substantiates these findings by showing a progressive decline in motor performance. Based on the comparisons made in this study in mice, the chronic MPTP/probenecid model shows considerable improvements over the conventional, subacute MPTP model. The sustained alterations in the nigrostriatal pathway resemble the cardinal signs of human Parkinson's disease and suggest that this chronic mouse model is potentially useful to study the pathophysiology and mechanisms of Parkinsonism. It should also prove useful for the development of neuroprotection strategies.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1996

Inner ear defect similar to Alport's syndrome in the glomerulosclerosis mouse model Mpv17.

The Mpv17 mouse strain is a recessive transgenic mouse mutant that develops glomerulosclerosis and nephrotic syndrome at a young age. The phenotype results from a loss of function of a gene coding for a hydrophobic peroxisomal protein of 176 amino acids of 20 kDa following its destruction by retroviral integration. To investigate a potential effect of the missing Mpv17 function on the inner ear light and electron microscopic investigations were performed on the inner ears of Mpv17 mice and controls. These revealed degeneration of the stria vascularis and spiral ligament, loss of cochlear neurons and degeneration of the organ of Corti. The alterations observed here were similar to those described for Alport's syndrome, an inherited disorder characterized by progressive nephritis and neurosensory deafness. These findings indicate that although the molecular cause is different, the Mpv17 mouse model may share pathological mechanisms involved in patients with Alport's syndrome. At present the Mpv17 mouse appears to be a suitable animal model for this disease and may help to further elucidate the relationship between the kidney and the inner ear.

Animals↗
PubMed2001

Autonomic dysreflexia in a mouse model of spinal cord injury.

Most experimental studies of spinal cord injury have centered on the rat as an experimental model. A shift toward a mouse model has occurred in recent years because of its usefulness as a genetic tool. While many studies have concentrated on motor function and the inflammatory response following spinal cord injury in the mouse, the development of autonomic dysreflexia after injury has yet to be described. Autonomic dysreflexia is a condition in which episodic hypertension develops after injuries above the mid-thoracic segment of the spinal cord. In this study 129Sv mice received a spinal cord transection at the second thoracic segment. The presence of autonomic dysreflexia was assessed 2 weeks later. Blood pressure responses to stimulation were as follows: moderate cutaneous pinch caudal to the injury (35+/-6 mm Hg), tail pinch (25+/-7 mm Hg), and a 0.3 ml balloon distension of the colon (37+/-4 mm Hg). Previous reports have suggested that small diameter primary afferent fiber sprouting after spinal cord injury may be responsible for the development of autonomic dysreflexia. In order to determine whether autonomic dysreflexia in the mouse may be caused by a similar mechanism, the size of the small diameter primary afferent arbor in spinal cord-injured and sham-operated animals was assessed by measuring the area occupied by calcitonin gene-related peptide-immunoreactive fibers. The percentage increase in the area of the small diameter primary afferent arbor in transected over sham-operated spinal cords was 46%, 45% and 80% at spinal segments thoracic T5-8, thoracic T9-12 and thoracic T13-lumbar L2 respectively. This study demonstrates the development of autonomic dysfunction in a mouse model of spinal cord injury that is associated with sprouting of calcitonin gene-related peptide fibers. These results provide strong support for the use of this mouse model of spinal cord injury in the study of autonomic dysreflexia.

Animals↗