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PubMed2000

Transgenic mouse models to study the role of the macrophage scavenger receptor class A in atherosclerosis.

Several in vivo studies have been performed on the role of the macrophage scavenger receptor class A (SR-A) in atherosclerosis using SR-A knockout mice. The results indicate both an antiatherogenic and a proatherogenic role of SR-A, depending on the nature of the animal model serving as the athero-susceptible background. To study the role of SR-A in a different model, we generated a transgenic mouse model with high level expression of the human SR-A gene using a 180 Kb yeast artificial chromosome (MSR1 transgenic mice). These mice show increased expression of SR-A according to the natural expression pattern. The MSR1 transgenic mice were crossed onto a low-density lipoprotein receptor deficient background and were fed a high fat diet for 10 weeks. After this period, the size of the atherosclerotic lesions in the proximal aorta was measured. Surprisingly, atherosclerosis was significantly reduced in the MSR1 transgenic mice. In a second study, the effect of SR-A was examined in APOE-3 Leiden mice providing a different athero-susceptible background. To exclude nonmacrophage effects, bone marrow was transplanted from MSR1 mice and wild-type littermates to APOE-3 Leiden transgenic mice. After 8 weeks on a high fat diet, atherosclerosis in the mice that had received MSR1 bone marrow was reduced compared with mice that had received wild-type bone marrow. This difference reached statistical significance when individual cholesterol exposure of the mice was taken into account. Both experiments indicated an antiatherogenic role of the SR-A. This observation cannot be explained easily by SR-A function in foam cell formation because in MSR1 macrophages in vitro foam cell formation is increased. Alternatively, however, SR-A may affect the activation of macrophages. Hence the response to lipopolysaccharide was measured in MSR1-transgenic macrophages. These macrophages showed a reduction in their activation in response to lipopolysaccharide, as measured by nitric oxide production. These data show that an elevated level of SR-A expression reduces atherosclerosis, potentially by modifying the response of macrophages to activation signals in the plaque.

Animals↗
PubMed1999

Behavioral effects of cocaine on a transgenic mouse model of cortical-limbic compulsion.

We previously created a transgenic mouse model of cortical-limbic induced compulsions in which dopamine D1 receptor-expressing (D1+) neurons in restricted regional subsets of the cortex and amygdala express a neuropotentiating cholera toxin (CT) transgene. These 'D1CT' mice engage in complex behavioral abnormalities uniquely resembling human compulsions, such as non-aggressive biting of cagemates during grooming, repeated leaping and episodes of perseverance of any and all normal behaviors. Because both compulsions and cocaine-induced behaviors may represent forms of psychomotor activation that have a shared or overlapping neurological basis, we have examined the behavioral response of these 'compulsive' mice to cocaine. In both control and D1CT mice, cocaine increased the amount of time spent engaged in typical cocaine-dependent stereotypies such as locomotion, sniffing, or gnawing, while the remainder of behaviors within their normally complete behavioral repertoires decreased. Cocaine also decreased, rather than facilitated, the incidence of D1CT transgene-induced compulsion-like behaviors such as repeated leaping and perseverance of any and all normal behaviors. The indistinguishable cocaine responses of D1CT and normal mice, as well as the masking (rather than potentiation) of D1CT mouse compulsion-like behaviors by cocaine, suggests that cortical-limbic induced compulsions are significantly different in their origin or circuitry from cocaine-induced stereotyped behaviors. Specifically, these data suggest that the motor circuits stimulated in compulsions represent only a subset of the parallel circuits stimulated by cocaine. These data are, thus, consistent with the hypothesis that topographically restricted subsets of parallel cortical-striatal-thalamic loops induce different types of compulsive behaviors.

Animals↗
PubMed2002

Instrumental activation of bid by caspase-1 in a transgenic mouse model of ALS.

Transgenic expression of mutant superoxide dismutase-1 (SOD1) produces an animal model of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. We have previously shown that the mitochondrial-dependent programmed cell death (PCD) pathway, including the redistribution of Bax, the cytosolic release of cytochrome c, and the activation of caspase-9, is recruited during neurodegeneration in spinal cords of transgenic mutant SOD1 mice. Herein, we show that the pro-PCD protein Bid is highly expressed in spinal cords of both wild-type and transgenic mutant SOD1 mice. While full-length Bid is found in the spinal cord of the two groups of mice, its cleaved form is only seen in transgenic mutant SOD1 mice, as early as the beginning of symptoms. In contrast, activated caspase-8, which is known to cleave Bid, is detected only at the end-stage of the disease. We also found that the expression of a dominant negative mutant of caspase-1 attenuates Bid cleavage as well as the mitochondrial release of cytochrome c, and the ensuing activation of caspase-9 and -3 in spinal cords of transgenic mutant SOD1 mice. These findings suggest that Bid cleavage may occur in this model by a pathway other than caspase-8 and shed light onto the molecular correlates of the previously reported beneficial effect of caspase-1 inhibition in transgenic mutant SOD1 mice.

Amyotrophic Lateral Sclerosis↗
PubMed1995

A transgenic mouse model (TG.AC) for skin carcinogenesis: inducible transgene expression as a second critical event.

The v-Ha-ras transgenic TG.AC mouse line behaves as a genetically initiated model for mouse skin tumorigenesis with enhanced susceptibility to skin carcinogens. TG.AC mice develop epidermal papillomas in fewer than 20 weeks in response to the topical application of a variety of chemicals such as complete carcinogens, phorbol ester-type tumor promoters, and nonphorbol ester-type tumor promoters as well as to full-thickness skin wounds or plucking of the dorsal hair. We have found that the pedunculated epidermal papillomas can arise as focal hyperplasias from the permanent portion of the follicular epithelium. Expression of the v-Ha-ras transgene serves as a marker for tumor development since it is expressed at significant levels in the papilloma precursors, focal follicular hyperplasias, and the papillomas but not in the surrounding skin. Transgene expression colocalizes with increased cell proliferation in the papillomas as compared to non-tumor bearing surrounding skin. Malignant skin tumors, primarily squamous cell carcinomas and sarcomas, develop from sites of papilloma development in approximately 40% of papilloma bearing mice. As well as significant levels of transgenic v-Ha-ras expression, some of the malignancies also exhibit karyotypic changes which include trisomy of chromosome six or fifteen, but not chromosome seven. We believe that the TG.AC mouse line serves not only as a model for studying the mechanisms of skin tumorigenesis, but will also be a useful adjunct to the two year NTP toxicity/carcinogenicity studies by identifying carcinogens in fewer than 20 weeks.

Animals↗
PubMed2001

Gender and aging in a transgenic mouse model of hypertrophic cardiomyopathy.

Mutations in the cardiac myosin heavy chain (MHC) can cause familial hypertrophic cardiomyopathy (FHC). A transgenic mouse model has been developed in which a missense (R403Q) allele and an actin-binding deletion in the alpha-MHC are expressed in the heart. We used an isovolumic left heart preparation to study the contractile characteristics of hearts from transgenic (TG) mice and their wild-type (WT) littermates. Both male and female TG mice developed left ventricular (LV) hypertrophy at 4 mo of age. LV hypertrophy was accompanied by LV diastolic dysfunction, but LV systolic function was normal and supranormal in the young TG females and males, respectively. At 10 mo of age, the females continued to present with LV concentric hypertrophy, whereas the males began to display LV dilation. In female TG mice at 10 mo of age, impaired LV diastolic function persisted without evidence of systolic dysfunction. In contrast, in 10-mo-old male TG mice, LV diastolic function worsened and systolic performance was impaired. Diminished coronary flow was observed in both 10-mo-old TG groups. These types of changes may contribute to the functional decompensation typically seen in hypertrophic cardiomyopathy. Collectively, these results further underscore the potential utility of this transgenic mouse model in elucidating pathogenesis of FHC.

Aging↗
PubMed2006

CD40 deficiency mitigates Alzheimer's disease pathology in transgenic mouse models.

We have previously shown that transgenic mice carrying a mutant human APP but deficient in CD40L, display a decrease in astrocytosis and microgliosis associated with a lower amount of deposited Abeta. Furthermore, an anti-CD40L treatment causes a diminution of Abeta pathology in the brain and an improved performance in several cognitive tasks in the double transgenic PSAPP mouse model. Although these data suggest a potential role for CD40L in Alzheimer's disease pathology in transgenic mice they do not cast light on whether this effect is due to inhibition of signaling via CD40 or whether it is due to the mitigation of some other unknown role of CD40L. In the present report we have generated APP and PSAPP mouse models with a disrupted CD40 gene and compared the pathological features (such as amyloid burden, astrocytosis and microgliosis that are typical of Alzheimer's disease-like pathology in these transgenic mouse strains) with appropriate controls. We find that all these features are reduced in mouse models deficient for CD40 compared with their littermates where CD40 is present. These data suggest that CD40 signaling is required to allow the full repertoire of AD-like pathology in these mice and that inhibition of the CD40 signaling pathway is a potential therapeutic strategy in Alzheimer's disease.

Journal Article↗
PubMed2005

Generation and characterization of a transgenic mouse model with hepatic expression of human CYP2A6.

The aim of this study was to prepare and characterize a transgenic mouse model in which CYP2A6, a human P450 enzyme, is expressed specifically in the liver. CYP2A6, which is mainly expressed in human liver, is active toward many xenobiotics. Our transgene construct contained the mouse transthyretin promoter/enhancer, a full-length CYP2A6 cDNA, and a downstream neomycin-resistance gene for positive selection in embryonic stem cells. Hepatic expression of the CYP2A6 transgene was demonstrated by immunoblotting, whereas tissue specificity of CYP2A6 expression was confirmed by RNA-PCR. The transgenic mouse was further characterized after being backcrossed to the B6 strain for six generations. Hepatic microsomes from homozygous transgenic mice had activities significantly higher than those of B6 mice toward coumarin. The in vivo activity of transgenic CYP2A6 was also determined. Systemic clearance of coumarin was significantly higher in the transgenic mice than in B6 controls, consistent with the predicted role of CYP2A6 as the major coumarin hydroxylase in human liver. The CYP2A6-transgenic mouse model should be valuable for studying the in vivo function of this polymorphic human enzyme in drug metabolism and chemical toxicity.

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↗
PubMed2005

A novel transgenic mouse model reveals humanlike regulation of an 8-kbp human TERT gene promoter fragment in normal and tumor tissues.

Telomerase activity is repressed in most human somatic tissues during differentiation processes but strongly up-regulated in most human tumors. Regulation of human telomerase activity primarily occurs at the level of transcriptional initiation of the TERT gene, which encodes the catalytic subunit of telomerase. We have generated a novel transgenic mouse model to study the regulation of the human TERT gene promoter in an in vivo system. For this purpose, we have cloned an 8.0-kbp human TERT promoter fragment in front of the bacterial lacZ reporter gene (hTERTp-lacZ), which encodes the beta-galactosidase enzyme. Expression of the reporter gene was monitored by reverse transcription-PCR analysis, 5-bromo-4-chloro-3-indolyl-beta-d-galactopyranoside staining of whole mount preparations, and histologic sections. We find that the activity of the human TERT promoter in most normal mouse tissues recapitulates the expression of the hTERT gene in normal human tissues and is under tighter control when compared with the endogenous mouse TERT gene expression. In testis, where highest lacZ expression was observed, the expression of the reporter gene was restricted to the spermatogonial stem cells and the spermatocytes. Intriguingly, we find increased levels of lacZ expression in mammary tumors of hTERTp-lacZ x p53(+/-) bitransgenic mouse mammary tumor model. Thus, this transgenic mouse model provides a suitable in vivo system to analyze the expression of the human TERT gene under physiologic conditions and during tumorigenesis.

Animals↗
PubMed2005

The use of the R6 transgenic mouse models of Huntington's disease in attempts to develop novel therapeutic strategies.

Huntington's disease (HD) is a genetic neurodegenerative disorder. Since identification of the disease-causing gene in 1993, a number of genetically modified animal models of HD have been generated. The first transgenic mouse models, R6/1 and R6/2 lines, were established 8 years ago. The R6/2 mice have been the best characterized and the most widely used model to study pathogenesis of HD and therapeutic interventions. In the present review, we especially focus on the characteristics of R6 transgenic mouse models and, in greater detail, describe the different therapeutic strategies that have been tested in these mice. We also, at the end, critically assess the relevance of the HD mouse models compared with the human disease and discuss how they can be best used in the future.

Animals↗
PubMed2006

Progressive alterations in the hypothalamic-pituitary-adrenal axis in the R6/2 transgenic mouse model of Huntington's disease.

Huntington's disease (HD) is characterized by a triad of motor, psychiatric and cognitive symptoms. Although many of these symptoms are likely to be related to central nervous system pathology, others may be due to changes in peripheral tissues. The R6/2 mouse, a transgenic model of HD expressing exon 1 of the human HD gene, develops progressive alterations in the hypothalamic-pituitary-adrenal axis, reminiscent of a Cushing-like syndrome. We observed muscular atrophy, reduced bone mineral density, abdominal fat accumulation and insulin resistance in the mice. All these changes could be consequences of increased glucocorticoid levels. Indeed, hypertrophy of the adrenal cortex and a progressive increase in serum and urine corticosterone levels were found in R6/2 mice. In addition, the intermediate pituitary lobe was markedly enlarged and circulating adreno-corticotrophic hormone (ACTH) increased. Under normal conditions dopamine represses the ACTH expression. In the R6/2 mice, however, the expression of pituitary dopamine D2 receptors was reduced by half, possibly explaining the increase in ACTH. Urinary samples from 82 HD patients and 68 control subjects were analysed for cortisol: in accord with the observations in the R6/2 mice, urinary cortisol increased in parallel with disease progression. This progressive increase in cortisol may contribute to the clinical symptoms, such as muscular wasting, mood changes and some of the cognitive deficits that occur in HD.

Adrenocorticotropic Hormone↗
PubMed2002

Elevated hepatic and depressed renal cytochrome P450 activity in the Tg2576 transgenic mouse model of Alzheimer's disease.

Recent studies indicate that the Tg2576 transgenic mouse model of Alzheimer's disease [tg(hAPP)] demonstrates disturbances in plasma glucose and neuroendocrine function reminiscent of Alzheimer's disease (AD). Alterations in any one of these systems can have a profound effect on hepatic cytochrome P450 (CYP) expression. Additionally, the recent discovery that amyloid beta 1-42 can induce the expression of CYP reductase in neuronal cultures further suggests that hepatic CYP-related metabolism may be affected by the expression of mutant human amyloid precursor protein in these tg(hAPP) mice. Therefore, the current study was conducted to investigate the activity and protein content of several CYP isoforms in the livers and kidneys of aged (20-month-old) tg(hAPP) mice. tg(hAPP) mice exhibit significant elevations in hepatic CYP2B, CYP2E1-, CYP3A- and CYP4A-associated activities and CYP4A immunoreactive protein compared with wild-type. In contrast to the liver, a significant depression in renal CYP2E1- and CYP4A-associated activities were demonstrated in tg(hAPP) mice. The presence of the mutant hAPP protein was detected in the brain, kidney and livers of tg(hAPP) mice.

Alzheimer Disease↗
PubMed2000

Up-regulation of cartilage oligomeric matrix protein at the onset of articular cartilage degeneration in a transgenic mouse model of osteoarthritis.

OBJECTIVE: To investigate the suitability of cartilage oligomeric matrix protein (COMP) as a marker for articular cartilage degeneration in a transgenic mouse model of osteoarthritis (OA). METHODS: Northern blot analysis of total RNA extracted from the knee joints of transgenic Del1 mice, which harbor a short deletion in a type II collagen transgene, and of their nontransgenic littermates was used to monitor changes in COMP messenger RNA (mRNA) levels during cartilage degeneration. Immunohistochemistry was used to determine the distribution of COMP in articular cartilage, and serum levels of COMP were measured by immunoassay. RESULTS: Transient up-regulation of COMP mRNA was seen in articular cartilage of transgenic Del1 mice at the onset of OA lesions at the age of 3 months. Compared with nontransgenic controls, COMP immunostaining of articular cartilage in 3-9-month-old transgenic mice was increased, especially at the border of uncalcified and calcified cartilage. There was also a change from predominantly interterritorial to pericellular/territorial deposition of COMP. This difference persisted until the age of 15 months, when the nontransgenic controls also demonstrated articular cartilage degeneration and increased COMP immunostaining. Increased serum levels of COMP were seen in Del1 mice at the age of 4 months, correlating temporally with the onset of cartilage degeneration. CONCLUSION: These findings suggest that upregulation of COMP mRNA and redistribution of the protein are characteristic of the early stages of articular cartilage degeneration in the transgenic mouse model in which OA results from a dominant-negative mutation in the type II collagen gene. The data provide additional support for the notion that COMP is a useful marker for altered cartilage metabolism in developing OA.

Animals↗
PubMed2005

Characterization of liver histopathology in a transgenic mouse model expressing genotype 1a hepatitis C virus core and envelope proteins 1 and 2.

Hepatitis C virus (HCV) is a major cause of chronic hepatitis and hepatocellular carcinoma worldwide. The purpose of this study was to determine how the HCV structural proteins affect the dynamic structural and functional properties of hepatocytes and measure the extra-hepatic manifestations induced by these viral proteins. A transgenic mouse model was established by expressing core, E1 and E2 proteins downstream of a CMV promoter. HCV RNA was detected using RT-PCR in transgenic mouse model tissues, such as liver, kidney, spleen and heart. Expression of the transgene was analysed by real-time PCR to quantify viral RNA in different tissues at different ages. Immunofluorescence analysis revealed the expression of core, E1 and E2 proteins predominantly in hepatocytes. Lower levels of protein expression were detected in spleen and kidneys. HCV RNA and viral protein expression increased in the liver with age. Histological analysis of liver cells demonstrated steatosis in transgenic mice older than 3 months, which was more progressed with age. Electron microscopy analysis revealed alterations in nuclei, mitochondria and endoplasmic reticulum. HCV structural proteins induce a severe hepatopathy in the transgenic mouse model. These mice became more prone to liver and lymphoid tumour development and hepatocellular carcinoma. In this model, the extra-hepatic effects of HCV, which included swelling of renal tubular cells, were mild. It is likely that the HCV structural proteins mediate some of the histological alterations in hepatocytes by interfering with lipid transport and liver metabolism.

Age Factors↗
PubMed2003

Skeletal muscle properties in a transgenic mouse model for amyotrophic lateral sclerosis: effects of creatine treatment.

The present study was undertaken to identify the metabolic and contractile characteristics of fast- and slow-twitch skeletal muscles in a transgenic mouse model of amyotrophic lateral sclerosis (ALS). In addition, we investigated the effects of oral creatine supplementation on muscle functional capacity in this model. Transgenic mice expressing a mutant (G93A) or wild type human SOD1 gene (WT) were supplemented with 2% creatine monohydrate from 60 to 120 days of age. Body weight, rotorod performance and grip strength were evaluated. In vitro contractility was evaluated on isolated m. soleus and m. extensor digitorum longus (EDL), and muscle metabolites were determined. Body weight, rotorod performance and grip strength were markedly decreased in G93A compared to WT mice, but were unaffected by creatine supplementation. Muscle ATP content decreased and glycogen content increased in G93A versus WT in both muscle types, but were unaffected by creatine supplementation. Muscle creatine content increased following creatine intake in G93A soleus. Twitch and tetanic contractions showed markedly slower contraction and relaxation times in G93A versus WT in both muscle types, with no positive effect of creatine supplementation. EDL but not soleus of G93A mice showed significant atrophy, which was partly abolished by creatine supplementation. It is concluded that overexpression of a mutant SOD1 transgene has profound effects on metabolic and contractile properties of both fast- and slow-twitch skeletal muscles. Furthermore, creatine intake does not exert a beneficial effect on muscle function in a transgenic mouse model of ALS.

Adenosine Triphosphate↗
PubMed1991

Towards a transgenic mouse model of sickle cell disease: hemoglobin SAD.

In order to obtain a transgenic mouse model of sickle cell disease, we have synthesized a novel human beta-globin gene, beta SAD, designed to increase the polymerization of the transgenic human hemoglobin S (Hb S) in vivo. beta SAD (beta S-Antilles-D Punjab) includes the beta 6Val substitution of the beta S chain, as well as two other mutations, Antilles (beta 23Ile) and D Punjab (beta 121Gln) each of which promotes the polymerization of Hb S in human. The beta SAD gene and the human alpha 2-globin gene, each linked to the beta-globin locus control region (LCR) were co-introduced into the mouse germ line. In one of the five transgenic lines obtained, SAD-1, red blood cells contained 19% human Hb SAD (alpha 2 human 1 beta 2SAD) and mouse-human hybrids in addition to mouse hemoglobin. Adult SAD-1 transgenic mice were not anemic but had some abnormal features of erythrocytes and slightly enlarged spleens. Their erythrocytes displayed sickling upon deoxygenation in vitro. SAD-1 neonates were anemic and many did not survive. In order to generate adult mice with a more severe sickle cell syndrome, crosses between the SAD progeny and homozygous for beta-thalassemic mice were performed. Hemoglobin SAD was increased to 26% in beta-thal/SAD-1 mice which exhibited: (i) abnormal erythrocytes with regard to shape and density; (ii) an enlarged spleen and a high reticulocyte count indicating an increased erythropoiesis; (iii) mortality upon hypoxia; (iv) polymerization of hemolysate similar to that obtained in human homozygous sickle cell disease; and (v) anemia and mortality during development.

Anemia, Sickle Cell↗
PubMed2005

Antidepressant action of agomelatine (S 20098) in a transgenic mouse model.

The aim of this study was to evaluate the efficacy of agomelatine (S 20098) to accelerate reversal of the neuroendocrinological, behavioural and cyclical changes seen in a transgenic mouse model of the neuroendocrine characteristics of depression. The effects of agomelatine were assessed in transgenic mice with low glucocorticoid receptor (GR) function, after acute stress or induced phase shift, and compared to desipramine and melatonin. Mice were injected 2 h before the onset of the dark period with agomelatine (10 mg/kg, i.p.), desipramine (10 mg/kg, i.p.), melatonin (10 mg/kg, i.p.) or vehicle (hydroxy-ethyl-cellulose (HEC) 1%) each day for 21 to 42 days. Agomelatine was effective in reversing the transgenic mouse behavioural changes noted in the Porsolt forced swim test as well as in the elevated plus maze. Both the number of open arm entries and the total time spent in open arms of the elevated plus maze is greatly increased in transgenic mice. The mean time spent in open arms is exquisitely sensitive to reversal by agomelatine and desipramine. Agomelatine also markedly accelerated readjustment of circadian cycles of temperature and activity following an induced phase shift. This action of agomelatine was superior to that of melatonin while desipramine was without effect. The accelerating effect of agomelatine was particularly notable if treatment was started 3 weeks prior to the induced phase shift. Agomelatine treatment did not cause any major change in corticosterone or adrenocorticotropic hormone (ACTH) concentrations nor in vasopressin (AVP), corticotropin-releasing hormone (CRH), GR and mineralocorticoid receptor (MR) mRNAs levels, which make it unlikely that the mechanism of agomelatine action is related to hypothalamic-pituitary-adrenocortical (HPA) axis changes. The present study shows that agomelatine displays some characteristics of antidepressant drug action in the transgenic mouse model, effects that could be partially related to its chronobiotic properties.

Acetamides↗