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PubMed1993

The influenza B virus mouse model of Reye's syndrome: pathogenesis of the hypoglycaemia.

Up to 40% of children with Reye's syndrome have hypoglycaemia that could contribute to the patient's encephalopathy. We developed a mouse model in which intravenous inoculation of influenza B/Lee virus produced a non-permissive infection of hepatocytes and cerebral endothelial cells and caused many clinical, biochemical and pathologic features of Reye's syndrome. We used this model to study the pathogenesis of the hypoglycaemia. Beginning 6 hours after virus inoculation and persisting to death 18-30 hours later, blood glucose levels fell by 40% and glycogen disappeared from the liver. Gluconeogenesis in liver slices from a pyruvate substrate was significantly impaired. Pyruvate carboxylase, normally present in hepatocyte mitochondria, was largely displaced into the cytosol, rendering that enzyme fraction relatively useless in the gluconeogenesis pathway. Brain glucose levels fell proportionately to the depressed blood glucose level to a mean of 44 mg/100 g compared to 108 mg/100 g in control brains. We conclude that hypoglycaemia in the mouse model developed largely as a result of a non-permissive influenza viral infection of hepatocytes which impaired the mitochondrial phase of gluconeogenesis. The hypoglycaemia may have contributed to, but did not solely account for, the encephalopathy. A similar non-permissive influenza B infection may cause hypoglycaemia in Reye's syndrome.

Animals↗
PubMed2004

White matter lesions and glial activation in a novel mouse model of chronic cerebral hypoperfusion.

BACKGROUND AND PURPOSE: Cerebrovascular white matter (WM) lesions are closely associated with cognitive impairment and gait disorders in the elderly. We have successfully established a mouse model of chronic cerebral hypoperfusion that may provide new strategies for the molecular analysis of cerebrovascular WM lesions. METHODS: Adult C57Bl/6 male mice were subjected to bilateral common carotid artery stenosis (BCAS) using external microcoils with varying inner diameters from 0.16 to 0.22 mm. Cerebral blood flow (CBF) in the frontal cortices was measured by laser-Doppler flowmetry at 2 hours and at 1, 3, 7, 14, and 30 days after BCAS. The brains were then removed and examined at 30 days with histological stains and immunohistochemistry for markers of microglia and astroglia. RESULTS: At 2 hours, the CBF values (ratio to the preoperative value) did not change in the 0.22 mm group but decreased significantly to 77.3+/-13.4% in the 0.20 mm group, 67.3+/-18.5% in the 0.18 mm group, and 51.4+/-11.5% in the 0.16 mm group. At day 1, the CBF began to recover in all groups but remained significantly lower until 14 days in comparison to the control group. In the 0.20 mm and 0.18 mm groups, WM lesions occurred after 14 days without any gray matter involvement. These lesions were the most intense in the corpus callosum adjacent to the lateral ventricle but were mild in the anterior commissure and optic tract. In contrast, 4 of 5 mice developed some gray matter changes in the 0.16 mm group. The proliferation of activated microglia and astroglia was observed in the WM beyond 3 days after BCAS. CONCLUSIONS: WM lesions were successfully induced after chronic cerebral hypoperfusion with relative preservation of the visual pathway. These features in this mouse model are appropriate for cognitive assessment and genetic analysis, and it may provide a powerful tool to understand the pathophysiology of WM lesions.

Animals↗
PubMed2004

Essential role of dendritic cell CD80/CD86 costimulation in the induction, but not reactivation, of TH2 effector responses in a mouse model of asthma.

BACKGROUND: Airway dendritic cells (DCs) are crucial for the generation of TH2 cells from naive T cells during sensitization and for reactivation of primed TH2 cells on allergen challenge in mouse models of asthma. It is unknown whether CD80/CD86 costimulation is necessary during both phases of the response because primed T cells rely less on costimulatory molecules compared with naive T cells. OBJECTIVE: We sought to study the contribution of CD80/CD86 costimulatory molecules on DCs during sensitization or challenge in a mouse model of asthma. METHODS: Naive BALB/c mice received an intratracheal injection of ovalbumin (OVA)-pulsed DCs obtained from the bone marrow of wild-type (WT) or CD80/CD86-/- mice and were subsequently challenged with OVA aerosol to address the role of costimulation during sensitization. OVA-sensitized mice received OVA-pulsed WT or CD80/CD86-/- DCs without OVA aerosol to address the role of costimulation during challenge. RESULTS: WT DCs induced the proliferation and effector TH2 differentiation of naive OVA-specific T cells, whereas CD80/CD86-/- DCs induced only proliferation. Not surprisingly, WT DCs but not CD80/CD86-/- DCs induced sensitization to OVA in naive mice. In contrast, in OVA-sensitized mice intratracheal injection of CD80/CD86-/- OVA-pulsed DCs led to eosinophilic airway inflammation, goblet cell hyperplasia, and effector TH2 cytokine production that was not different from that seen after injection with WT OVA-DCs, even when the inducible costimulator ICOS was blocked or cytotoxic T lymphocyte-associated antigen 4 immunoglobulin was given. CONCLUSION: CD80/CD86 costimulation on DCs is only necessary during priming of naive T cells into TH2 cells but not during restimulation of previously primed TH2 cells in the challenge phase.

Animals↗
PubMed2005

A gene-targeted mouse model for chorea-acanthocytosis.

Chorea-acanthocytosis (CHAC) is a hereditary neurodegenerative disorder with autosomal recessive transmission, in which selective degeneration of striatum has been reported in brain pathology. Clinically, CHAC shows Huntington's disease-like neuropsychiatric symptoms and red blood cell acanthocytosis. Recently, we identified the gene, CHAC, encoding a novel protein, chorein, in which a deletion mutation was found in Japanese families with CHAC. In the present study, we have identified the mouse CHAC cDNA sequence and the exon-intron structures of the gene and produced a CHAC model mouse introducing no. 60-61 exon deletion corresponding to a human disease mutation by a gene-targeting technique. The mice began to show acanthocytosis and motor disturbance in old age. In behavioral observations, locomotor activity was significantly decreased and the contact time at social interaction test was decreased significantly in the model mice. In the brain pathology, many apoptotic cells were observed in the striatum of the mutant mice. In neurochemical determinations, the dopamine metabolite, homovanillic acid, concentration decreased significantly in the portion including the midbrain of the mutant mice. These findings are consistent with the human results reported elsewhere and indicate that the CHAC model mice showed a mild phenotype with late adult onset. The CHAC model mouse therefore provides a good model system to study the human disease.

Acanthocytes↗
PubMed1998

Generalized glycogen storage and cardiomegaly in a knockout mouse model of Pompe disease.

Glycogen storage disease type II (GSDII; Pompe disease), caused by inherited deficiency of acid alpha-glucosidase, is a lysosomal disorder affecting heart and skeletal muscles. A mouse model of this disease was obtained by targeted disruption of the murine acid alpha-glucosidase gene (Gaa) in embryonic stem cells. Homozygous knockout mice (Gaa -/-) lack Gaa mRNA and have a virtually complete acid alpha-glucosidase deficiency. Glycogen-containing lysosomes are detected soon after birth in liver, heart and skeletal muscle cells. By 13 weeks of age, large focal deposits of glycogen have formed. Vacuolar spaces stain positive for acid phosphatase as a sign of lysosomal pathology. Both male and female knockout mice are fertile and can be intercrossed to produce progeny. The first born knockout mice are at present 9 months old. Overt clinical symptoms are still absent, but the heart is typically enlarged and the electrocardiogram is abnormal. The mouse model will help greatly to understand the pathogenic mechanism of GSDII and is a valuable instrument to explore the efficacy of different therapeutic interventions.

Animals↗
PubMed2005

Molecular characterization of salivary gland malignancy using the Smgb-Tag transgenic mouse model.

The molecular mechanisms underlying salivary gland tumorigenesis remain unclear. In order to identify genetic changes that occur during the development of invasive adenocarcinoma from normal salivary gland, we used the Smgb-Tag transgenic mouse model. This transgene induces the progressive development of dysplasia to invasive adenocarcinoma in the submandibular salivary gland. Gene expression patterns from 20 submandibular glands (two normal, nine dysplasia and nine adenocarcinoma samples) were assessed using a mouse 15 K cDNA array. Unsupervised hierarchical clustering was used to group gene expression based on 157 differentially expressed genes distinguishing between dysplasias and adenocarcinomas. Further analysis identified 25 significantly overexpressed and 28 underexpressed cDNA sequences in adenocarcinoma as compared to dysplasia. Differential expression of five genes (Lcn2, Ptn, Cd24a, Mapk6 and Rnps1) was validated by quantitative real-time RT-PCR in a total of 48 mouse salivary gland tissues (seven histologically normal, 13 dysplasias and 28 adenocarcinomas), including the 20 samples analyzed by cDNA arrays. Immunohistochemical analysis was used to validate the expression of Ptn and Cd24a at the protein level in a subset of 16 mouse salivary glands (four normal, five dysplasia and seven adenocarcinoma samples), as well as in 23 human submandibular gland tumors (16 pleomorphic adenomas, three adenoid cystic carcinomas, one acinic cell carcinoma, one adenocarcinoma NOS, one myoepithelial and one mucoepidermoid carcinoma). We thus demonstrated that the Smgb-Tag transgenic mouse model is a useful tool for the identification of genes that are deregulated in salivary gland adenocarcinomas. Our data suggest that Ptn and Cd24a may be genetic markers associated with salivary gland tumorigenesis and/or progression.

Adenocarcinoma↗
PubMed2001

Spontaneous hemorrhagic stroke in a mouse model of cerebral amyloid angiopathy.

A high risk factor for spontaneous and often fatal lobar hemorrhage is cerebral amyloid angiopathy (CAA). We now report that CAA in an amyloid precursor protein transgenic mouse model (APP23 mice) leads to a loss of vascular smooth muscle cells, aneurysmal vasodilatation, and in rare cases, vessel obliteration and severe vasculitis. This weakening of the vessel wall is followed by rupture and bleedings that range from multiple, recurrent microhemorrhages to large hematomas. Our results demonstrate that, in APP transgenic mice, the extracellular deposition of neuron-derived beta-amyloid in the vessel wall is the cause of vessel wall disruption, which eventually leads to parenchymal hemorrhage. This first mouse model of CAA-associated hemorrhagic stroke will now allow development of diagnostic and therapeutic strategies.

Aging↗
PubMed2002

Sex does not seem to influence the formation of aortic lesions in the P-407-induced mouse model of hyperlipidemia and atherosclerosis.

Coronary heart disease secondary to atherosclerosis is the leading cause of death for men in the United States. Using a new, nontransgenic, non-fat-fed mouse model of hyperlipidemia and atherosclerosis developed in our laboratory, we investigated the effect of sex on lipid profiles and subsequent aortic atherosclerotic lesion formation. Female and male C57BL/6 mice, which consumed a low-fat diet, were treated with either normal saline or poloxamer 407 (P-407), a triblock copolymer comprised of poly(oxyethylene) and poly(oxypropylene) units, for 4 months. Blood samples were obtained at 0, 1, 2, 3, and 4 months, whereas hearts and livers were harvested only at 4 months, because this model requires approximately 4 months for significant atheroma formation. P-407-treated mice of either sex demonstrated a profound increase in plasma cholesterol and triglyceride; at 3 and 4 months the plasma lipids were significantly (p < 0.05) higher for male mice compared with female mice. Aortas retrieved from P-407-treated mice of either sex after 4 months demonstrated a significant (p < 0.001) increase in the mean atherosclerotic lesion size compared with their respective saline-treated controls, but there was no significant (p > 0.05) difference between lesion sizes for P-407-treated male mice (1.02 +/- 0.074 x 10(5) microm(2)) compared with P-407-treated female mice (1.14 +/- 0.28 x 10(5) microm(2)). Livers harvested at 4 months from either sex of P-407-treated mice displayed no damage to hepatocytes but increased proliferation of macrophages (Kupffer cells), which contained sequestered lipids. Thus, male C57BL/6 mice form atherosclerotic lesions as extensive as female mice in the P-407 mouse model of atherosclerosis.

Animals↗
PubMed1998

A mouse model of acute bacterial rhinosinusitis.

OBJECTIVE: To develop a mouse model of acute bacterial rhinosinusitis. DESIGN: Study mice (C57BL6/J) were inoculated intranasally with Streptococcus pneumoniae, ATCC 49619 suspended in trypticase soy broth, and controls were inoculated with trypticase soy broth alone. After 2, 5, or 14 days, intranasal cultures were obtained and mice were killed. The sinuses were prepared for histological investigation. SETTING: Animal care facility at a tertiary, academic institution. METHOD: The histological sections of the sinuses were examined in a blinded manner for the percentage of sinus cavity occupied by neutrophil clusters, and for the number of neutrophils per square millimeter of sinus mucosa. RESULTS: Infected mice killed at 5 days had significantly more sinus area occupied by neutrophil clusters, significantly more neutrophils within the mucosa, and significantly more S pneumoniae growth in the intranasal cultures compared with controls (15/15 vs 0/6; P<.01). The amount of inflammation had decreased at 2 weeks. CONCLUSION: Streptococcus pneumoniae induces acute bacterial rhinosinusitis in C57BL6/4 mice as measured by culture and influx of neutrophils, and can be used as a model of acute bacterial rhinosinusitis.

Animals↗
PubMed1993

BSB: a new mouse model of multigenic obesity.

We report here a new mouse model of multigenic obesity. Backcross progeny ((C57BL/6J x Mus spretus)F1 x C57BL/6J), designated as BSB mice, range from 1% to 50% body fat. Since both parental strains are relatively lean, the wide range of the phenotype in the BSB mice indicates the involvement of multiple genes to produce obesity. Obesity in BSB mice results from increases in both intra-abdominal and subcutaneous fat and is associated with hyperinsulinemia, hyperglycemia, and hyperlipidemia. Female and male BSB mice do not differ in the degree of obesity obtained. Stimulated plasma corticosterone levels are reduced in obese male and female mice. The development of appropriate genetic markers and statistical methods have made it feasible to analyze quantitative polygenic traits in animal models by employing F2 or backcross progeny. Thus, this BSB model is uniquely suited to the genetic analysis of the multifactorial quantitative trait of obesity and its associated phenotypes.

Animals↗
PubMed2005

Male sex aggravates the phenotype in mouse models of hypertrophic cardiomyopathy.

The authors have created transgenic mouse models of hypertrophic cardiomyopathy with mutations in either cardiac troponin T or myosin heavy chain. Mice mutant in myosin heavy chain develop significant cardiac hypertrophy at young adult age. Female mice keep that hypertrophic state, whereas male mice undergo progressive dilatation and exhibit systolic dysfunction at older age. Mice mutant in troponin, however, exhibit no baseline hypertrophy. When put under chronic adrenergic stress, all male mice die suddenly, whereas female mice show no mortality. These examples highlight the aggravated phenotype in male mice modeling hypertrophic cardiomyopathy and are a starting point to new mechanistic experiments.

Animals↗
PubMed2006

Early diabetes-induced biochemical changes in the retina: comparison of rat and mouse models.

AIMS/HYPOTHESIS: Recently, various transgenic and knock-out mouse models have become available for studying the pathogenesis of diabetic retinopathy. At the same time, diabetes-induced retinal changes in the wild-type mice remain poorly characterised. The present study compared retinal biochemical changes in rats and mice with similar (6-week) durations of streptozotocin-induced diabetes. MATERIALS AND METHODS: The experiments were performed on Wistar rats and C57Bl6/J mice. Retinal glucose, sorbitol, fructose, lactate, pyruvate, glutamate, alpha-ketoglutarate and ammonia were measured spectrofluorometrically by enzymatic methods. Vascular endothelial growth factor (VEGF) protein was assessed by ELISA, and poly(ADP-ribosyl)ation by immunohistochemistry and western blot analysis. Free mitochondrial and cytosolic NAD(+)/NADH ratios were calculated from the glutamate and lactate dehydrogenase systems. RESULTS: Retinal glucose concentrations were similarly increased in diabetic rats and mice, vs controls. Diabetic rats manifested approximately 26- and 5-fold accumulation of retinal sorbitol and fructose, respectively, whereas elevation of both metabolites in diabetic mice was quite modest. Correspondingly, diabetic rats had (1) increased retinal malondialdehyde plus 4-hydroxyalkenal concentrations, (2) reduced superoxide dismutase (SOD), glutathione peroxidase, glutathione reductase and glutathione transferase activities, (3) slightly increased poly(ADP-ribose) immunoreactivity and poly(ADP-ribosyl)ated protein abundance, and (4) VEGF protein overexpression. Diabetic mice lacked these changes. SOD activity was 21-fold higher in murine than in rat retinas (the difference increased to 54-fold under diabetic conditions), whereas other antioxidative enzyme activities were 3- to 10-fold lower. With the exception of catalase, the key antioxidant defence enzyme activities were increased, rather than reduced, in diabetic mice. Diabetic rats had decreased free mitochondrial and cytosolic NAD(+)/NADH ratios, consistent with retinal hypoxia, whereas both ratios remained in the normal range in diabetic mice. CONCLUSIONS/INTERPRETATION: Mice with short-term streptozotocin-induced diabetes lack many biochemical changes that are clearly manifest in the retina of streptozotocin-diabetic rats. This should be considered when selecting animal models for studying early retinal pathology associated with diabetes.

Animals↗
PubMed2002

Humanized mouse models of FcR clearance in immune platelet disorders.

Transgenic mouse lines expressing physiologic levels of human platelet Fc receptor (FcR) for IgG, Fc gamma RIIA, on platelets and macrophages were generated. Anti-CD9 antibody activated platelets of Fc gamma RIIA transgenic mice and, following injection in vivo, caused rapid and severe thrombocytopenia compared with nonactivating antiplatelet antibody. Anti-CD9 injected in Fc gamma RIIA transgenic mice crossed with FcR gamma-chain knockout (gamma-KO) mice caused thrombosis and shock in all mice, and death in 16 of 18 mice. Histologic examination of lung vasculature of anti-CD-treated Fc gamma RIIA transgenic x gamma-KO mice showed extensive platelet-fibrin thrombi. Taken together, these observations suggest that in Fc gamma RIIA transgenic x gamma-KO mice there is an important interplay of intravascular platelet activation and splenic clearance. Reduction of splenic clearance surgically or functionally also facilitated anti-CD-9-mediated shock in Fc gamma RIIA transgenic mice. Thus, antibodies that activate platelets in an Fc gamma RIIA-dependent manner lead to thrombosis, shock, and death. These mouse model findings have implications for human immune-mediated thrombocytopenic disorders. Genetic factors may be important in the interindividual variability seen clinically, and with nonactivating platelet antibody the spleen is largely responsible for the thrombocytopenia. This is likely the case in typical idiopathic thrombocytopenic purpura (ITP). For several other immune thrombocytopenic disorders, the spleen probably plays a second, protective role in removing antibody-coated platelets from the circulation.

Animals↗
PubMed2005

A knock-in mouse model of gastrointestinal stromal tumor harboring kit K641E.

A mouse model of gastrointestinal stromal tumor (GIST) has been developed by a knock-in gene targeting strategy, which introduced a Kit gene K641E mutation, originally identified in sporadic human GISTs and in the germ line of familial GIST syndrome patients. Homozygous and heterozygous Kit K641E mice develop gastrointestinal pathology with complete penetrance and all Kit K641E homozygotes die by age 30 weeks due to gastrointestinal obstruction by hyperplastic interstitial cells of Cajal (ICC) or GISTs. Heterozygous mice have less extensive ICC hyperplasia and smaller GISTs, suggesting a dose-response relationship between oncogenically activated Kit and ICC proliferation. Immunoprecipitation and Western blotting reveal GISTs to contain abundant phosphorylated/activated Kit. In addition to ICC hyperplasia and GISTs, homozygous Kit K641E mice exhibit loss-of-function Kit phenotypes, including white coat color, decreased numbers of dermal mast cells, and sterility, indicating that despite its oncogenic activity the mutant form cannot accomplish many activities of the wild-type gene. Kit K641E reproduces the pathology associated with the familial GIST syndrome and thus is an excellent model to study Kit pathway activation, ICC biology, GIST pathogenesis, and preclinical validations of GIST therapies and mechanisms of drug resistance.

Alleles↗
PubMed2003

Long-term stable expression of human apolipoprotein A-I mediated by helper-dependent adenovirus gene transfer inhibits atherosclerosis progression and remodels atherosclerotic plaques in a mouse model of familial hypercholesterolemia.

BACKGROUND: Epidemiologic studies and transgenic mouse experiments indicate that high plasma HDL and apolipoprotein (apo) A-I protect against atherosclerosis. We used helper-dependent adenovirus (HD-Ad) gene transfer to examine the effect of long-term hepatic apoA-I expression on atherosclerotic lesion progression and remodeling in a mouse model of familial hypercholesterolemia. METHODS AND RESULTS: We treated LDL receptor-deficient (LDLR-/-) mice maintained on a high-cholesterol diet for 6 weeks with either a HD-Ad containing human apoA-I gene (HD-Ad-AI) or saline (control). HD-Ad-AI treatment did not affect plasma liver enzymes but induced the appearance of plasma human apoA-I at or above human levels for the duration of the study. Substantial amounts of human apoA-I existed in lipid-free plasma. Compared with controls, HDLs from treated mice were larger and had a greater inhibitory effect on tumor necrosis factor-alpha-induced vascular cellular adhesion molecule-1 expression in cultured endothelial cells. Twenty-four weeks after injection, aortic atherosclerotic lesion area in saline-treated mice progressed approximately 700%; the rate of progression was reduced by >50% by HD-Ad-AI treatment. The lesions in HD-Ad-AI-treated mice contained human apoA-I that colocalized mainly with macrophages; they also contained less lipid, fewer macrophages, and less vascular cellular adhesion molecule-1 immunostaining but more smooth muscle cells (alpha-actin staining) and collagen. CONCLUSIONS: HD-Ad-AI treatment of LDLR-/- mice leads to long-term overexpression of apoA-I, retards atherosclerosis progression, and remodels the lesions to a more stable-appearing phenotype. HD-Ad-mediated transfer of apoA-I may be a useful clinical approach for protecting against atherosclerosis progression and stabilizing atherosclerotic lesions associated with dyslipidemia in human patients.

Adenoviridae↗
PubMed2005

Nuclear factor-kappaB affects tumor progression in a mouse model of malignant pleural effusion.

We developed a novel mouse model of malignant pleural effusion (MPE) by injecting Lewis lung cancer (LLC) cells directly into the pleural space of syngeneic C57B/6 mice. The pleural effusions in this model share common cellular and biochemical features with human MPEs. Implantation and growth of pleural tumors triggers a host inflammatory response characterized by a mixed inflammatory cell influx into the pleural fluid. LLC cells exhibited high basal nuclear factor (NF)-kappaB activity in vitro and in vivo, which we used to drive expression of a NF-kappaB-dependent green fluorescent protein-firefly luciferase fusion reporter construct. NF-kappaB-dependent reporter expression allowed intravital tracing of pleural tumors. Inhibition of NF-kappaB in LLC cells did not affect cell viability in culture; however, injection of LLC cells expressing a dominant NF-kappaB inhibitor resulted in decreased tumor burden, decreased pleural effusion volume, and decreased pleural effusion TNF-alpha levels. These studies indicate that tumor NF-kappaB activity regulates pleural tumor progression. This reproducible model of MPE can be used to further study the influence of specific host and tumor factors on the pathogenesis of MPE and evaluate new therapeutic strategies.

Animals↗
PubMed1986

Experimental nude mouse model of human colorectal cancer liver metastases.

A nude mouse model (BALB/c) was established for investigating the production of hepatic metastases by human colorectal carcinoma (HCC) cells. The malignant potentials of 3 different HCCs derived from a primary tumor (HCC-P4733), a lymph node metastasis (HCC-M14328), and a hepatic metastasis (HCC-M1410) were investigated following implantation into the spleens of athymic nude mice. Cells of the HCC-M1410 line produced extensive liver tumors in all mice by 30 days after injection. Cells of the HCC-M14328 and HCC-P4733 lines produced few liver tumors in the inoculated mice and then only after a 90-day period. Isozyme and karyotype analyses ascertained the human origin of all the tumors. Studies with [125I]IdUrd-labeled HT-29 carcinoma cells suggested that tumor cells reached the liver shortly after injection into the spleen. Thus the production of HCC tumors in livers of nude mice was determined by the ability of HCC cells to proliferate in the liver parenchyma rather than by the ability of the cells to reach the liver. The results suggest that the intrasplenic injection of HCC cells can provide a valuable model for the study of the biology and therapy of the liver metastases.

Animals↗