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PubMed1997

Demonstration of two different processes of beta-cell regeneration in a new diabetic mouse model induced by selective perfusion of alloxan.

To clarify the regeneration process of pancreatic beta-cells, we established a new mouse model of diabetes induced by selective perfusion of alloxan after clamping the superior mesenteric artery. In this model, diabetes could be induced by the destruction of beta-cells in alloxan-perfused segments, while beta-cells in nonperfused segments were spared. Intraperitoneal glucose tolerance tests showed glucose intolerance, which gradually ameliorated and was completely normalized in 1 year with a concomitant increase of insulin content in the pancreas. Histological examination showed neo-islet formation in the alloxan-perfused segment and the proliferation of spared beta-cells in the nonperfused segment. In the alloxan-perfused segment, despite a marked reduction of islets in size and number at an early stage, both the number of islets, including islet-like cell clusters (ICCs), and the relative islet area significantly increased at a later stage. Increased single beta-cells and ICCs were located in close contact with duct cell lining, suggesting that they differentiated from duct cells and that such extra-islet precursor cells may be important for beta-cell regeneration in beta-cell-depleted segment. In addition to beta-cells, some nonhormone cells in ICCs were positive for nuclear insulin promoter factor 1, which indicated that most, if not all, nonhormone cells positive for this factor were beta-cell precursors. In the nonperfused segment, the islet area increased significantly, and the highest 5-bromo-2-deoxyuridine-labeling index in beta-cells was observed at day 5, while the number of islets did not increase significantly. This indicated that the regeneration of islet endocrine cells occurs mostly through the proliferation of preexisting intra-islet beta-cells in the nonperfused segment. In conclusion, the regeneration process of beta-cells varied by circumstance. Our mouse model is useful for studying the mechanism of regeneration, since differentiation and proliferation could be analyzed separately in one pancreas.

Alloxan↗
PubMed2005

Behavioral assessment in mouse models of neuronal ceroid lipofuscinosis using a light-cued T-maze.

Learning impairment is a common feature of the neuronal ceroid lipofuscinoses (NCL), a family of lysosomal storage disorders associated with progressive neurodegeneration. Murine models for the neuronal ceroid lipofuscinoses include the well-characterized motor neuron degeneration (mnd/mnd) model for one variant of late infantile NCL (CLN8), and the more recently generated models for the infantile (CLN1) and juvenile (CLN3) forms of NCL. To determine whether these mouse models exhibit behavioral deficits analogous to the learning impairment characteristic of the human disorders, the performance of these animals on an associative learning task was assessed. The abilities of affected and normal control mice to associate a light stimulus with a food reward were evaluated in 14-16-week-old animals using a T-maze. Normal mice were able to reach a criterion for having learned to make the association within a mean of 9.4 trials. The CLN8 and CLN3 mice, on the other hand, required means of 26.2 and 27.5 trials, respectively, to reach the same performance criterion (p<0.05), whereas none of the CLN1 mice were able to reach the criterion within a limit of 30 trials. The poor performance of the mutant mice did not appear to result from impaired retinal function; mice of all three strains exhibited retinal electrophysiological responses to dim light flashes and displayed robust pupillary light reflexes. Associative learning deficits appear to be an early disease phenotype in the NCL mouse models that will be useful for assessing the efficacy of therapeutic interventions such as gene or stem cell therapies.

Analysis of Variance↗
PubMed1999

A mouse model utilising human transferrin to study protection against Neisseria meningitidis serogroup B induced by outer membrane vesicle vaccination.

We have previously developed a mouse model based on transient bacteraemia in normal B10.M mice to evaluate the protective efficacy of outer membrane vesicle vaccines against serogroup B meningococci. To obtain a course of infection similar to that observed in man, we have in this work modified the mouse model by administration of human holo-transferrin upon bacterial challenge. Co-challenge with holo-transferrin induced increasing bacteraemia and subsequent death in normal non-immune mice, but not in vaccinated animals. The model system is dependent on challenge with meningococci expressing the transferrin receptor which is obtained by culturing the bacteria under iron restriction. The modified model system for protection against meningococcal infection presented here makes it possible to measure outer membrane vesicle vaccine induced protection by using bacteraemia as well as survival as parameters.

Animals↗
PubMed1986

A mouse model for the study of necrotizing enterocolitis.

A mouse model for the study of necrotizing enterocolitis is presented. It is a model of temporary intestinal ischemia and consists of occluding both superior mesenteric vessels with a bulldog clamp for varying periods of time. The resultant lesions resemble the intestinal lesions seen in necrotizing enterocolitis in respect to the gradual development of the necrotizing lesions and their patchy distribution. We also studied the effect of intravenous saline and low molecular weight dextran in preventing the development of these ischemic lesions. In moderate ischemia, saline and dextran show a similar protective effect, and in severe ischemia, both show a protective effect, with dextran being more effective than saline.

Animals↗
PubMed2002

A mouse model of neuropathic cancer pain.

We developed a mouse model of neuropathic cancer pain by inoculating Meth A sarcoma cells to the immediate proximity of the sciatic nerve in BALB/c mice. The tumor grows predictably with time and gradually compresses the nerve, thereby causing nerve injury. Time courses of thermal hyperalgesia and mechanical sensitivity to von Frey hairs were determined and signs of spontaneous pain were evaluated. We compared this model with the chronic constriction injury (CCI) model, which is a neuropathic pain model widely utilized in the rat. Furthermore, to characterize the difference in nerve injury between the two models, we performed histological examination of the nerve of the two models by light and electron microscopy. Progressive compression of the sciatic nerve by growth of a tumor mass resulted in a gradual development of thermal hyperalgesia and mechanical allodynia in the ipsilateral hind paw. Signs of spontaneous pain, such as lifting of the paw, were also observed. However, further growth of the tumor reversed the mechanical hypersensitivity and produced mechanical hyposensitivity, while thermal hyperalgesia and signs of spontaneous pain still persisted. Histologically, gradual compression by the tumor resulted in a progressive damage to both myelinated and unmyelinated fibers. However, the severity of damage to the myelinated fibers was considerably less compared to that of the CCI mice. In the CCI mice, severe damage to myelinated fibers, especially large fibers, was observed and unmyelinated fibers were damaged to a lesser degree. These results suggest that gradual compression of a nerve by a malignant tumor results in nerve damage with a profile considerably different from that of chronic constriction injury produced by loose ligation of the nerve. Our new tumor model may be useful in studies of neuropathic cancer pain due to nerve compression by malignant tumors.

Animals↗
PubMed2000

SEREX analysis for tumor antigen identification in a mouse model of adenocarcinoma.

Evaluation of immunotherapy strategies in mouse models of carcinoma is hampered by the limited number of known murine tumor antigens (Ags). Although tumor Ags can be identified based on cytotoxic T-cell activation, this approach is not readily accomplished for many tumor types. We applied an alternative strategy based on a humoral immune response, SEREX, to the identification of tumor Ags in the murine colon adenocarcinoma cell line MC38. Immunization of syngeneic C57BL/6 mice with MC38 cells by three different methods induced a protective immune response with concomitant production of anti-MC38 antibodies. Immunoscreening of an MC38-derived expression library resulted in the identification of the endogenous ecotropic leukemia virus envelope (env) protein and the murine ATRX protein as candidate tumor Ags. Northern blot analysis demonstrated high levels of expression of the env transcript in MC38 cells and in several other murine tumor cell lines, whereas expression in normal colonic epithelium was absent. ATRX was found to be variably expressed in tumor cell lines and in normal tissue. Further analysis of the expressed env sequence indicated that it represents a nonmutated tumor Ag. Polynucleotide immunization with DNA encoding the env polypeptide resulted in strong and specific antibody responses to this self Ag in all immunized mice. Thus, SEREX offers a rapid means of identifying tumor Ags in murine cancer models.

Adenocarcinoma↗
PubMed1999

Enhanced sensitivity to N-methyl-D-aspartate receptor activation in transgenic and knockin mouse models of Huntington's disease.

We used two mouse models of Huntington's disease (HD) to examine changes in glutamate receptor sensitivity and striatal electrophysiology. One model, a transgenic, consisted of mice expressing exon 1 of the human HD gene and carrying 141-157 CAG repeat sequences (R6/2 line). The second model, a CAG repeat "knockin," consisted of mice with different lengths of CAG repeats (CAG71 and CAG94 repeats). The effects of glutamate receptor activation were examined by visualizing neurons in brain slices with infrared videomicroscopy and differential interference contrast optics to determine changes in somatic area (cell swelling). Striatal and cortical neurons in both models (R6/2 and CAG94) displayed more rapid and increased swelling to N-methyl-D-aspartate (NMDA) than those in controls. This effect was specific as there were no consistent group differences after exposure to alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) or kainate (KA). Intracellular recordings revealed that resting membrane potentials (RMPs) in the R6/2 transgenics were significantly more depolarized than those in their respective controls. RMPs in CAG94 mice also were more depolarized than those in CAG71 mice or their controls in a subset of striatal neurons. Confirming previous results, R6/2 mice expressed behavioral abnormalities and nuclear inclusions. However, CAG71 and CAG94 knockins did not, suggesting that increased sensitivity to NMDA may occur early in the disease process. These findings imply that NMDA antagonists or compounds that alter sensitivity of NMDA receptors may be useful in the treatment of HD.

Animals↗
PubMed1992

A mouse model of coxsackievirus myocarditis.

OBJECTIVE: To develop a mouse model of coxsackievirus B3 (CVB3) myocarditis. DESIGN: Preliminary studies have indicated that mice infected with CVB3 alone erratically responded with viral myocarditis. Prospective evaluation of the effect of cyclophosphamide at two time intervals resulted in consistency for the development of myocarditis. ANIMALS: Juvenile five- to nine-week-old male mice CD-1 type (Charles River Canada Limited). INTERVENTIONS: Infection with coxsackie B3 enterovirus. Pretreatment with cyclophosphamide two days and 4 h before inoculation of 0.2 or 0.15 mg/g. Animals were killed seven, nine, 28 and 63 days post infection. MAIN RESULTS: Following cyclophosphamide conditioning, a tissue response infection with CVB3 was uniformly observed. Virus, however, was infrequently recovered from the myocardium whereas myocarditis became chronic after 28 days. CONCLUSIONS: Pretreatment of juvenile mice with cyclophosphamide results in a reproducible model of viral myocarditis with chronic changes in the myocardium.

Animals↗
PubMedDate not supplied

Evaluation of the neurotoxicity of dapsone in the mouse model.

Effect of DDS was studied using the mouse model. It was observed that DDS did not have any neurotoxic effect. On the contrary it showed a protective action towards the nerve, when administered in the early stages following definite establishment of nerve lesions.

Animals↗
PubMedDate not supplied

Orthotopic SCID mouse model with two newly established human lung squamous carcinoma cell lines.

The objective of this study was to present an orthotopic SCID mouse model using two newly established human cell lines derived from squamous cell carcinomas of the lung. GO-LCC1 cells (1 x 10(6)) and GO-LCC2 cells (3 x 10(6)) were implanted orthotopically into the right lungs of 10 C.B. 17 scid/scid mice. In both groups, aggressive tumor growth with partial infiltration of the thoracic wall, heart and diaphragm was observed. In only one case distant metastases in the contralateral lung were detected, while all animals developed tumors at the site of inoculation. Xenografted GO-LCC1 cells showed enhanced tumor propagation compared to GO-LCC2 cells. Our data underscore the usefulness of the SCID mouse model to study the biological behaviour of cultuved human tumor cells and furthemore demonstrate the clinical applicability of xenograft techniques using human tumor cell lines derived from pneumonectomy specimens of squamous lung carcinomas.

Animals↗
PubMed2003

Mouse models as a tool for understanding neurodegenerative diseases.

PURPOSE OF REVIEW: The purpose of this review is to present recent advances in the both the creation and the use of mouse models of human neurodegenerative disease. We briefly touch on the technologies used to make these models, and then focus on recent results from new models. We discuss why such models are useful when they do - and do not - mimic the human disorder. RECENT FINDINGS: The numbers of mouse models are increasing dramatically and are starting to yield important results for human disease. We present a selection of new and important models and the results of recent investigations of these animals. SUMMARY: An accepted protocol when studying any form of human neurodegenerative disease is to investigate the genetics, pathology, neurophysiology, response to therapeutics, etc., of the disorder in the mouse. This approach is clearly bearing fruit for our understanding and treatment of human neurodegeneration.

Animals↗
PubMed2003

A mouse model of severe acute pancreatitis induced with caerulein and lipopolysaccharide.

AIM: To establish a non-traumatic, easy to induce and reproducible mouse model of severe acute pancreatitis (SAP) induced with caerulein and lipopolyasccharide (LPS). METHODS: Thirty-two healthy mature NIH female mice were selected and divided at random into four groups (each of 8 mice), i.e., the control group (NS group), the caerulein group (Cn group), the lipopolysaccharide group (LPS group), and the caerulein+LPS group (Cn+LPS group). Mice were injected intraperitoneally with caerulein only, or LPS only, and caerulein and LPS in combination. All the animals were then killed by neck dislocation three hours after the last intraperitoneal injection. The pancreas and exo-pancreatic organs were then carefully removed for microscopic examination. And the pancreatic acinus was further observed under transmission electron microscope (TEM). Pancreatic weight, serum amylase, serum nitric oxide (NO) concentration, superoxide dismutase (SOD) and malondialdehyde (MDA) concentration of the pancreas were assayed respectively. RESULTS: (1) NS animals displayed normal pancreatic structure both in the exocrine and endocrine. In the LPS group, the pancreas was slightly edematous, with the infiltration of a few inflammatory cells and the necrosis of the adjacent fat tissues. All the animals of the Cn group showed distinct signs of a mild edematous pancreatitis characterized by interstitial edema, infiltration of neutrophil and mononuclear cells, but without obvious parenchyma necrosis and hemorrhage. In contrast, the Cn+LPS group showed more diffuse focal areas of nonviable pancreatic and hemorrhage as well as systemic organ dysfunction. According to Schmidt's criteria, the pancreatic histologic score showed that there existed significant difference in the Cn+LPS group in the interstitial edema, inflammatory infiltration, parenchyma necrosis and parenchyma homorrhage in comparison with those of the Cn group, LPS group and NS group (P<0.01 or P<0.05). (2) The ultrasturcture of acinar cells was seriously damaged in the Cn+LPS group. Chromatin margination of nuclei was present, the number and volume of vacuoles greatly increased. Zymogen granules (ZGs) were greatly decreased in number and endoplasmic reticulum exhibited whorls. The swollen mitochondria appeared, the crista of which was decreased in number or disappeared. (3) Pancreatic weight and serum amylase levels in the Cn +LPS was significantly higher than those of the NS group and the LPS group respectively (P<0.01 or P<0.05). However, the pancreatic wet weight and serum amylase concentration showed no significant difference between the Cn+LPS group and the Cn group. (4) NO concentration in the Cn+LPS group was significantly higher than that of NS group, LPS group and Cn group(P<0.05 or P<0.01). (5) The SOD and MDA concentration of the pancreas in the Cn+LPS group were significantly higher than those of NS, LPS and Cn groups (P<0.05 or P<0.01). CONCLUSION: The mouse model of severe acute pancreatitis could be induced with caerulein and LPS, which could be non-traumatic and easy to induce, reproducible with the same pathological characteristics as those of SAP in human, and could be used in the research on the mechanism of human SAP.

Acute Disease↗
PubMed1999

Intramuscular grafts of myoblasts genetically modified to secrete glial cell line-derived neurotrophic factor prevent motoneuron loss and disease progression in a mouse model of familial amyotrophic lateral sclerosis.

Effects of ex vivo GDNF gene delivery on the degeneration of motoneurons were studied in the G1H transgenic mouse model of familial ALS carrying a human superoxide dismutase (SOD1) with a Gly93Ala mutation (Gurney et al., 1994). Retroviral vectors were made to produce human GDNF or E. coli beta-galactosidase (beta-Gal) by transient transfection of the Phoenix cell line and used to infect primary mouse myoblasts. In 6-week-old G1H mice, 50,000 myoblasts per muscle were injected bilaterally into two hindlimb muscles. Untreated G1H and wild-type mice served as additional controls. At 17 weeks of age, 1 week before sacrifice, these muscles were injected with fluorogold (FG) to retrogradely label spinal motoneurons that maintained axonal projections to the muscles. There were significantly more large FG-labeled alpha motoneurons at 18 weeks in GDNF-treated G1H mice than in untreated and beta-Gal-treated G1H mice. A morphometric study of motoneuron size distribution showed that GDNF shifted the size distribution of motoneurons toward larger cells compared with control G1H mice, although the average size and number of large motoneurons in GDNF-treated mice were less than that in wild-type mice. GDNF also prolonged the onset of disease, delayed the deterioration of performance in tests of motor behavior, and slowed muscle atrophy. Quantitative, real-time RT-PCR and PCR showed persistence of transgene mRNA and DNA in muscle for up to 12 weeks postgrafting. These observations demonstrate that ex vivo GDNF gene therapy in a mouse model of FALS promotes the survival of functional motoneurons, suggesting that a similar approach might delay the progression of neurodegeneration in ALS.

Amyotrophic Lateral Sclerosis↗
PubMed2004

In vivo MRI of embryonic stem cells in a mouse model of myocardial infarction.

The therapeutic potential of administering stem cells to promote angiogenesis and myocardial tissue regeneration after infarction has recently been demonstrated. Given the advantages of using embryonic stem cells and mouse models of myocardial infarction for furthering the development of this therapeutic approach, the purpose of this study was to determine if embryonic stem cells could be loaded with superparamagnetic iron oxide (SPIO) particles and imaged in a mouse model of myocardial infarction over time using MRI. Mouse embryonic stem cells were labeled with SPIO particles. When incubated with 11.2, 22.4, and 44.8 microg Fe/ml of SPIO particles, cells took up increasing amounts of iron oxide. Embryonic stem cells loaded with SPIO compared to unlabeled cells had similar viability and proliferation profiles for up to 14 days. Free SPIO injected into infarcted myocardium was not observable within 12 hr after injection. After injection of three 10-microl aliquots of 10(7) SPIO-loaded cells/ml into infarcted myocardium, MRI demonstrated that the mouse embryonic stem cells were observable and could be seen for at least 5 weeks after injection. These findings support the ability of MRI to test the long-term therapeutic potential of embryonic stem cells in small animals in the setting of myocardial infarction.

Animals↗
PubMed2004

Detection of amyloid plaques in mouse models of Alzheimer's disease by magnetic resonance imaging.

We performed three-dimensional, high-resolution magnetic resonance imaging (MRI) of fixed mouse brains to determine whether MRI can detect amyloid plaques in transgenic mouse models of Alzheimer's disease. Plaque-like structures in the cortex and hippocampus could be clearly identified in T2-weighted images with an image resolution of 46 microm x 72 microm x 72 microm. The locations of plaques were confirmed in coregistration studies comparing MR images with Congo red-stained histological results. This technique is quantitative, less labor-intensive compared to histology, and is free from artifacts related to sectioning process (deformation and missing tissues). It enabled us to study the distribution of plaques in the entire brain in 3D. The results of this study suggest that this method may be useful for assessing treatment efficacy in mouse models of Alzheimer's disease (AD).

Alzheimer Disease↗
PubMed1992

Histopathologic-microbiologic correlates of invasiveness in a mouse model of ascending unobstructed urinary tract infection.

To clarify the usefulness of histopathology in evaluating invasiveness during acute cystitis and pyelonephritis in a mouse model of urinary tract infection, findings from bladder and kidney sections of mice inoculated transurethrally with Escherichia coli were compared with results of bladder, kidney, spleen, and blood cultures and with changes in peripheral blood leukocyte counts. All of the 14 bladder histopathologic abnormalities evaluated were significantly associated with a positive bladder culture, and 7 were associated with splenic infection. Histopathologic features of cystitis were present in some culture-negative bladders. Eleven of 12 renal histopathologic abnormalities evaluated were significantly associated both with a positive kidney culture and with splenic infection, and two correlated with the development of peripheral leukocytosis. Histopathologic features of pyelitis and nephritis permitted culture-positive kidneys to be categorized as exhibiting colonization only, pyelitis only, or pyelitis plus frank nephritis and demonstrated that some culture-negative kidneys exhibit signs of pyelitis and nephritis. These findings suggest that detailed, semiquantitative histopathologic evaluation can add to quantitative cultures in the assessment of bacterial urovirulence in the mouse model of ascending urinary tract infection.

Animals↗
PubMed1998

Induction of somatic intrachromosomal recombination inversion events by cyclophosphamide in a transgenic mouse model.

Somatic intrachromosomal recombination (SICR) can result in chromosomal inversion and deletion, mechanisms which are important in carcinogenesis. We have utilised a transgenic mouse model to study SICR inversion events in spleen cells. The transgenic construct is designed so that expression of an Escherichia coli lacZ transgene only occurs in a cell when an SICR inversion event occurs in the region of the transgene. The inversion events can then be detected by histochemical staining of frozen spleen sections for transgene expression and by polymerase chain reaction across the inversion breakpoints. The spontaneous inversion frequency in spleen rose 2-fold from 1.54 +/- 0.24 x 10(-4) (mean +/- SE) in 4-month-old transgenic mice to 3.12 +/- 0.67 x 10(-4) in 22-month-old mice. Four- or 8-month-old mice were treated with a single intraperitoneal injection of cyclophosphamide, with doses ranging from 0.01 to 100 mg/kg. The animals were killed 3 days after treatment. A significant induction of SICR inversions was detected at all doses with a 3.2-fold maximum induction of inversions detected at 10 mg/kg. These results suggest that the transgenic mouse model used here may be a sensitive model for studying the role of SICR in mutation and in studying risk assessment of environmental DNA-damaging agents.

Animals↗
PubMed2003

Comparative analysis of cervical cancer in women and in a human papillomavirus-transgenic mouse model: identification of minichromosome maintenance protein 7 as an informative biomarker for human cervical cancer.

Human papillomaviruses (HPVs), such as HPV-16, are associated with >99% of cervical cancers in women. Two viral oncogenes, E6 and E7, are selectively expressed in these cancers. K14E6 and K14E7 transgenic mouse strains, which express the HPV16 E6 or E7 gene in stratified squamous epithelia, display many acute and long-term phenotypes indicative of the oncogenic potential of E6 and E7 including epithelial hyperplasia, abrogation of normal DNA damage responses, and spontaneous skin tumors. When treated with estrogen, these HPV-16 transgenic mice develop a progressive disease leading to cervical cancer that shows many histopathological parallels to cervical cancer in women. In this study, we evaluated the cervical lesions that arise in these transgenic mice for the expression of biomarkers induced in human cervical cancer. These analyses, which showed close parallels in the timing and pattern of expression of cyclin E and Ki-67 in the mouse cervical disease compared with that in humans, provided further validation of this HPV-16 transgenic mouse model for human cervical cancer. We then used our mouse model to identify minichromosome maintenance protein 7 (MCM7), an E2F-induced cellular DNA replication factor, as a novel biomarker for cervical cancer. In both the mouse and human disease, strong, full thickness staining for MCM7 was seen selectively in the epithelium of high-grade intraepithelial lesions and in frank cancer. The uniform staining pattern and strong signal for MCM7 suggest that MCM7 may be a highly informative biomarker for cervical cancer.

Animals↗