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PubMed1991

Pathogenesis of AIDS-associated Kaposi's sarcoma.

Kaposi's sarcoma (KS) is a mesenchymal tumor of unclear etiopathogenesis. The epidemic form of KS occurs in up to 30% of HIV-infected individuals with lesions that have mixed cellularity, spindle cell proliferation, and neoangiogenesis. Although not completely defined, the spindle cells, thought to be the tumor cells of KS, are of mesenchymal cell origin, with features resembling endothelial and smooth muscle cells. The establishment of in vitro and in vivo model systems (AIDS-KS cell culture and the transgenic mouse model) for KS have allowed studies of the pathogenesis of KS. In particular, studies of the biologic characteristics of the AIDS-KS cells have demonstrated the presence of autocrine and paracrine growth activities. The findings of specific cytokines produced by the AIDS-KS cells may explain the histologic changes found in the KS lesion. Similarly, the development of KS-like lesions by inoculating cultured AIDS-KS cells into nude mice suggests that KS is an inducible disease. Finally, the results obtained in tat-transgenic mice and the proliferative induction of AIDS-KS cells by addition of exogenous (cell-released or recombinant) Tat protein suggest that this HIV gene product may have an important role in the development or progression of KS in HIV-infected individuals.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Quantitative evaluation of left ventricular function in a TransgenicMouse model of dilated cardiomyopathy with 2-dimensional contrast echocardiography.

The study of transgenic mouse models of human cardiovascular disease has been limited by the small size and high heart rate of the mouse heart. Advances in digital echocardiographic imaging equipment have provided the high spatial and temporal resolution necessary for 2-dimensional (2D) in vivo imaging of the mouse heart. The goal of this study was to test the use of contrast-enhanced 2D echocardiography to quantitatively assess left ventricular (LV) size and function in normal and transgenic mice with dilated cardiomyopathy. Images were obtained with a 12-MHz broadband transducer in the parasternal short-axis view in 8 control mice and 8 transgenic mice with dilated cardiomyopathy resulting from expression of a dominant-negative CREB transcription factor in the heart. LV opacification was achieved with injections of human albumin microspheres, injectable suspension (Optison) (15 to 30 microliter bolus). LV area was measured throughout the cardiac cycle with manual frame-by-frame tracing of the endocardial boundary. End-systolic and end-diastolic areas (ESA and EDA) were measured and fractional area change (FAC) calculated in both groups at baseline and during administration of dobutamine (40 microgram/kg/min intravenously). High-quality 2D images, which yielded LV area over time waveforms, were obtained in all mice. Under baseline conditions, ESA was significantly higher and FAC lower in the transgenic mice compared with their controls. During administration of dobutamine, normal mice had significantly smaller ESA and significantly larger FAC compared with baseline conditions, whereas this trend did not reach significance in the transgenic mice. In summary, quantitative assessment of LV size and function may be achieved with contrast-enhanced 2D echocardiographic imaging. This technique promises to facilitate studies of pathophysiology in murine models of human cardiovascular disease.

Animals↗
PubMed1996

Dissecting megakaryocytopoiesis in vivo with toxigenes.

The genetic programs that regulate the commitment of a totipotent stem cell to the megakaryocytic lineage remain poorly defined and require appropriate in vivo models. Using a cell-specific obliteration technique, a transgenic mouse model was produced where perturbations of megakaryocytopoiesis and platelet production may be induced on demand. This was achieved by targeting the expression of the herpes virus thymidine kinase (HSV-tk) to megakaryocytes using the regulatory regions of the gene coding for the alphaIIb gene, an early marker of megakaryocytopoiesis, which encodes the alpha subunit of the platelet integrin alphaIIb beta3. The HSV-tk gene is not toxic by itself, but sensitizes the target cell to the effect of ganciclovir (GCV), leading to the inhibition of DNA synthesis in dividing cells. The programmed eradication of the megakaryocytic lineage was induced by treating transgenic mice bearing the hybrid construct (alphaIIb-tk) with GCV. After 10 days of treatment, the platelet number was reduced by greater than 96.5% and megakaryocytes were not detectable in the bone marrow (BM). After discontinuing GCV, BM was repopulated with megakaryocytes, and the platelet count was restored within seven days. The recovery was accelerated by the administration of interleukin 11. Prolonged GCV treatment induced erythropenia in the transgenic mice. Assays of myeloid progenitor cells in vitro demonstrated that the transgene was expressed in early erythro-megakaryocytic bipotent progenitor cells. The reversibility and facility of this system provide a powerful model to determine both the critical events in megakaryocytic and erythroid lineage development, and for evaluating the precise role that platelets play in the pathogenesis of a number of vascular occlusive disorders.

Animals↗
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↗
PubMed1991

Role of serum amyloid P component for systemic amyloidosis in transgenic mice carrying human mutant transthyretin gene.

The role of serum amyloid P component (SAP) for systemic amyloidosis in a transgenic mouse model for an autosomal dominant disease, familial amyloidotic polyneuropathy (FAP), was examined. For this purpose, two lines of transgenic mouse were produced by introducing the human mutant transthyretin (TTR) gene and the human SAP gene, respectively. Two lines of transgenic mice were mated to produce double transgenic mice carrying both human mutant TTR gene and human SAP gene. The serum concentration of human SAP in these transgenic mice was about 42 micrograms/ml and was about equal to that in human control serum. In case of single transgenic mice carrying human mutant TTR gene, amyloid deposition starts at around 6 months of age, and the amount of amyloid deposition increases gradually with age. Amyloid deposition is observed in many tissues including heart, kidney and thyroid gland, where amyloid deposition is commonly observed in FAP patients. In double transgenic mice, onset, progression and tissue distribution of amyloid deposition were the same as those in single transgenic mouse. These results clearly suggest that SAP is not important for the initiation and progression of amyloid deposition.

Age Factors↗
PubMed2002

A mouse model for immunotherapy of myeloma.

Myeloma cells secrete monoclonal immunoglobulin (Ig), called myeloma protein. The variable (V) regions of myeloma proteins are unique to each plasma cell tumor, and therefore contain highly tumor-specific antigenic determinants called idiotopes (Id). In ongoing clinical trials, myeloma patients are vaccinated against the Id of their own myeloma protein. T cells with specificity for Id are thought to be of importance in eradication of multiple myeloma. We have developed a mouse model to study the molecular and cellular mechanisms for how Id-specific T cell protect against myeloma. A T cell receptor (TCR) transgenic mouse model has been established. CD4+ T cells in these mice recognize a particular Id-peptide presented on a MHC class II molecule. The Id-peptide represents an 11-mere of the variable region L chain of a particular mouse myeloma, MOPC315. TCR-transgenic mice are protected against a challenge with MOPC315 cells. Id-specific CD4+ cells protect in the absence of anti-Id antibodies. Dendritic cells in s.c. tumors take up myeloma protein and present Id-peptide on class II molecules to CD4+ cells which become activated and then kill bystander myeloma cells by an unknown mechanism. When TCR-transgenic mice are injected with large amounts of MOPC315 myeloma cells, resistance is overcome and some 30% of mice develop tumors. In these mice, Id-specific T cells become deleted as the myeloma protein serum concentration exceeds 50 microg/ml. In conclusion, in an experimental model, Id-specific CD4+ T cells protect against myeloma. However, once a tumor is established, Id-specific T cells become incapacitated. Based on these results, it is suggested that Id-vaccination in humans should be reserved for eradication of minimal residual disease, eg after high dose chemotherapy and stem cell transplantation.

Animals↗
PubMed2002

Tauroursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington's disease.

Huntington's disease (HD) is an untreatable neurological disorder caused by selective and progressive degeneration of the caudate nucleus and putamen of the basal ganglia. Although the etiology of HD pathology is not fully understood, the observed loss of neuronal cells is thought to occur primarily through apoptosis. Furthermore, there is evidence in HD that cell death is mediated through mitochondrial pathways, and mitochondrial deficits are commonly associated with HD. We have previously reported that treatment with tauroursodeoxycholic acid (TUDCA), a hydrophilic bile acid, prevented neuropathology and associated behavioral deficits in the 3-nitropropionic acid rat model of HD. We therefore examined whether TUDCA would also be neuroprotective in a genetic mouse model of HD. Our results showed that systemically administered TUDCA led to a significant reduction in striatal neuropathology of the R6/2 transgenic HD mouse. Specifically, R6/2 mice began receiving TUDCA at 6 weeks of age and exhibited reduced striatal atrophy, decreased striatal apoptosis, as well as fewer and smaller size ubiquitinated neuronal intranuclear huntingtin inclusions. Moreover, locomotor and sensorimotor deficits were significantly improved in the TUDCA-treated mice. In conclusion, TUDCA is a nontoxic, endogenously produced hydrophilic bile acid that is neuroprotective in a transgenic mouse model of HD and, therefore, may provide a novel and effective treatment in patients with HD.

Animals↗
PubMed1993

Stimulation of the collagen alpha 1 (I) endogenous gene and transgene in carbon tetrachloride-induced hepatic fibrosis.

Cirrhosis is characterized by a marked increase in the deposition of type I collagen and in the expression of the type I collagen genes alpha 1(I) and alpha 2(I). Although alpha 1(I) gene regulation has been extensively studied in cultured cells, these results may not be applicable to hepatic fibrogenesis in vivo. Therefore the regulation of the alpha 1(I) endogenous gene and an alpha 1(I) transgene was studied in a transgenic mouse model that has a single copy of a human alpha 1(I) gene segment containing the structural gene and 1.6 Kb of 5' DNA and 20 Kb of 3' DNA. To initiate hepatic fibrogenesis, we treated mice with the hepatotoxin carbon tetrachloride, either in a single dose or in biweekly doses for a period of 3 to 8 wk. Subsequently, hepatic alpha 1(I) messenger RNA levels were determined by a species-specific RNase protection assay. Carbon tetrachloride injections coordinately increased the messenger RNA levels of the alpha 1(I) endogenous gene and the transgene, both immediately and after 8 wk. These experiments demonstrate that this alpha 1(I) transgene fragment contains information sufficient for appropriate basal and carbon tetrachloride-stimulated hepatic expression. They further demonstrate that sufficient homology exists between the human and mouse regulatory elements for the recognition of human cis-acting elements by mouse trans-acting factors. Thus transgenic mice provide a unique model in which to characterize the collagen alpha 1(I) regulatory elements that are required in vivo for pathophysiological responses.

Animals↗
PubMed2002

Hyperekplexia: a treatable neurogenetic disease.

Hyperekplexia is primarily an autosomal dominant disease characterized by exaggerated startle reflex and neonatal hypertonia. It can be associated with, if untreated, sudden infant death from apnea or aspiration pneumonia and serious injuries and loss of ambulation from frequent falls. Different mutations in the alpha1 subunit of inhibitory glycine receptor (GLRA1) gene have been identified in many affected families. The most common mutation is Arg271 reported in at least 12 independent families. These mutations uncouple the ligand binding and chloride channel function of inhibitory glycine receptor and result in increased excitability in pontomedullary reticular neurons and abnormal spinal reciprocal inhibition. Three mouse models from spontaneous mutations in GLRA1 and beta subunit of inhibitory glycine receptor (GLRB) genes and two transgenic mouse models are valuable for the study of the pathophysiology and the genotype-phenotype correlation of the disease. The disease caused by mutation in GLRB in mice supports the notion that human hyperekplexia with no detectable mutations in GLRA1 may harbor mutations in GLRB. Clonazepam, a gamma aminobutyric acid (GABA) receptor agonist, is highly effective and is the drug of choice. It enhances the GABA-gated chloride channel function and presumably compensates for the defective glycine-gated chloride channel in hyperekplexia. Recognition of the disease will lead to appropriate treatment and genetic counseling.

Animals↗
PubMed2007

Keratin 18 overexpression but not phosphorylation or filament organization blocks mouse Mallory body formation.

UNLABELLED: Several human liver diseases are associated with formation of Mallory body (MB) inclusions. These hepatocyte cytoplasmic deposits are composed primarily of hyperphosphorylated keratins 8 and 18 (K8/K18). Feeding a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-containing diet is a well-established mouse model of MBs. K8 overexpression, and K8-null or K18-null mouse models, indicate that a K8-greater-than-K18 expression ratio is critical for MB formation. We used established transgenic mouse models to study the effect of K18 overexpression and phosphorylation, or keratin filament disorganization, on MB formation. Five mouse lines were used: nontransgenic, those that overexpress wild-type K18 or the K18 phosphorylation mutants Ser33-to-Ala (S33A) or Ser52-to-Ala (S52A), and mice that overexpress K18 Arg89-to-Cys, which causes collapse of the keratin filament network into dots. DDC feeding induced MBs in nontransgenic livers, but MBs were rarely seen in any of the K18 transgenic mice. Wild-type K18 overexpression protected mice from DDC-induced liver injury. CONCLUSION: K18 overexpression protects mice from MB formation and from DDC-induced liver injury, which supports the importance of the K8-to-K18 ratio in MB formation. The effect of K18 on MB formation is independent of hepatocyte keratin filament organization or K18 Ser33/Ser52 phosphorylation. Keratin filament collapse, which is a major risk for acute liver injury, is well tolerated in the context of chronic DDC-mediated liver injury.

Animals↗
PubMed1991

Modifications in the organization and expression of collagen genes associated with skeletal disorders.

Fibril-forming collagens represent an evolutionary related group of structurally similar molecules within the larger family of collagen proteins. Characterization of naturally occurring mutations has provided a model whereby clinically distinct phenotypes are predicted on the basis of how specific mutations alter normal fibrillogenesis. This model, originally derived from studies of type I collagen defects in osteogenesis imperfecta and Ehlers Danlos syndrome type VII, has been modified and extended by recent correlations of type II collagen defects with several chondrodysplasias and of type III collagen defects with Ehlers Danlos syndrome type IV. From analysis of the skeletal dysplasias, the pathogenic role of fibrillar collagen defects in more common clinical entities has been suggested and awaits rigorous proof. Although informative, these collective studies have revealed important exceptions to predictions of the original pathobiochemical paradigm, and, thus, they have initiated a more rigorous reconsideration of the deductive model. As an alternative, investigations are currently underway to generate transgenic mouse models of human collagenopathies. This task will not only clarify the complexity of collagen pathophysiology, but it will also permit the development of therapeutic strategies.

Animals↗
PubMed2004

Brain-derived neurotrophic factor regulates the onset and severity of motor dysfunction associated with enkephalinergic neuronal degeneration in Huntington's disease.

The mechanism that controls the selective vulnerability of striatal neurons in Huntington's disease is unclear. Brain-derived neurotrophic factor (BDNF) protects striatal neurons and is regulated by Huntingtin through the interaction with the neuron-restrictive silencer factor. Here, we demonstrate that the downregulation of BDNF by mutant Huntingtin depends on the length and levels of expression of the CAG repeats in cell cultures. To analyze the functional effects of these changes in BDNF in Huntington's disease, we disrupted the expression of bdnf in a transgenic mouse model by cross-mating bdnf(+/ -) mice with R6/1 mice. Thus, we compared transgenic mice for mutant Huntingtin with different levels of BDNF. Using this double mutant mouse line, we show that the deficit of endogenous BDNF modulates the pathology of Huntington's disease. The decreased levels of this neurotrophin advance the onset of motor dysfunctions and produce more severe uncoordinated movements. This behavioral pathology correlates with the loss of striatal dopamine and cAMP-regulated phosphoprotein-32-positive projection neurons. In particular, the insufficient levels of BDNF cause specific degeneration of the enkephalinergic striatal projection neurons, which are the most affected cells in Huntington's disease. This neuronal dysfunction can specifically be restored by administration of exogenous BDNF. Therefore, the decrease in BDNF levels plays a key role in the specific pathology observed in Huntington's disease by inducing dysfunction of striatal enkephalinergic neurons that produce severe motor dysfunctions. Hence, administration of exogenous BDNF may delay or stop illness progression.

Age of Onset↗
PubMed2006

Dormant Wnt-initiated mammary cancer can participate in reconstituting functional mammary glands.

The minimal residual disease foci that beget breast cancer relapse after a period of disease dormancy remain uncharacterized despite their enormous clinical importance. To model dormant breast cancer in vivo, we employed a transgenic mouse model in which Wnt1-initiated mammary cancer is doxycycline dependent. After regression of Wnt-dependent cancers, subclinical disease lesions were propagated in vivo using classical tissue recombination techniques. Surprisingly, outgrowths derived from dormant malignant tissue reconstituted morphologically normal ductal trees in wild-type mammary fat pads. Whereas hyperplasia-derived outgrowths remained benign, outgrowths derived from dormant malignancy underwent a morphological transition suggesting single-step transformation following reactivation of Wnt signaling and rapidly yielded invasive mammary tumors. Remarkably, outgrowths derived from dormant malignancy could be serially propagated in vivo and retained the potential to undergo lobuloalveolar differentiation in response to hormones of pregnancy. Matching somatic H-Ras mutations shared by antecedent tumors and descendant mammary ductal outgrowths confirmed their clonal relatedness. Thus, propagation of epithelium that possesses a latent malignant growth program reveals impressive regenerative and developmental potential, supporting the notion that dormant mammary cancers harbor transformed mammary progenitor cells. Our results define an experimental paradigm for elucidating biological properties of dormant malignancy.

Animals↗
PubMed2005

APP23 mice as a model of Alzheimer's disease: an example of a transgenic approach to modeling a CNS disorder.

Animal models are considered essential in research ensuing elucidation of human disease processes and subsequently, testing of potential therapeutic strategies. This is especially true for neurodegenerative disorders, in which the first steps in pathogenesis are often not accessible in human patients. Alzheimer's disease is vastly becoming a major medical and socioeconomic problem in our aging society. Valid animal models for this uniquely human condition should exhibit histopathological, biochemical, cognitive, and behavioral alterations observed in Alzheimer's disease patients. Major progress has been made since the understanding of the genetic basis of Alzheimer's disease and the development and improvement of transgenic mouse models. All present Alzheimer's disease models developed are partial but nevertheless essential in further unraveling the nature and spatial and temporal development of the complex molecular pathology underlying this condition. One of the more recent transgenic attempts to model Alzheimer's disease is the APP23 transgenic mouse. This article describes the development and assessment of this human amyloid precursor protein overexpression model. We summarize histopathological and biochemical, cognitive and behavioral observations made in heterozygous APP23 mice, thereby emphasizing the model's contribution to clarification of neurodegenerative disease mechanisms. In addition, the first therapeutic interventions in the APP23 model are included.

Alzheimer Disease↗
PubMed2005

Pathophysiology of pituitary adenomas.

Pituitary tumor initiation and progression are associated with a plethora of genetic imbalances. The role of pituitary trophic status as determinant of neoplastic potential is not clear. The pituitary gland responds to diverse central and peripheral signals by undergoing reversible plastic and functional changes. The resulting hyperplasia/excess hormone production, or involution/hyposecretion in pituitary cells may correlate with the ability to develop pituitary tumors. It is difficult to test this hypothesis, in part due to limitations on the definition of human pituitary cell trophic status and because this organ is not readily accessible for serial histopathological analysis. Therefore, animal models represent the most functional approach to testing this hypothesis. Transgenic mouse models of pituitary tumor transforming gene (PTTG) inactivation or overexpression support the notion that a permissive trophic environment may be required for pituitary tumor formation. Mechanisms underlying changes in pituitary plasticity and their relationship to tumor development may account for the diverse genetic abnormalities observed in pituitary tumors.

Adenoma↗
PubMed2006

Implication of pituitary tropic status on tumor development.

Pituitary tumor initiation and progression are associated with a plethora of genetic imbalances. Several genetic abnormalities have been described in pituitary tumors, from mutations in intracellular signaling (constitutive activation adenylyl cyclase) and growth factor pathways (epidermal growth factor receptor [EGFR]) to imbalance in cell cycle regulators (p16, p27, pRb). Unfortunately, most of these observations do not provide validated predictors of clinical behavior or of recurrence. The pituitary gland is notably plastic, and intrinsic and extrinsic stimuli result in profound growth changes ranging from hypoplasia to hyperplasia. The impact of pituitary tropic status on influencing neoplastic potential is difficult to test in human samples because the gland is not readily accessible for ongoing morphological observation. Animal models represent a functional approach to testing this hypothesis, and transgenic mouse models of pituitary tumor transforming gene (PTTG) inactivation or overexpression support the notion that pituitary tropic status directly correlates with likelihood for pituitary tumor formation. Understanding the mechanisms underlying changes in pituitary plasticity and their relationship to tumor development may contribute to the ability of regulating the development and progression of pituitary tumors.

Animals↗
PubMed2005

A ketogenic diet reduces amyloid beta 40 and 42 in a mouse model of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that primarily strikes the elderly. Studies in both humans and animal models have linked the consumption of cholesterol and saturated fats with amyloid-beta (Abeta) deposition and development of AD. Yet, these studies did not examine high fat diets in combination with reduced carbohydrate intake. Here we tested the effect of a high saturated fat/low carbohydrate diet on a transgenic mouse model of AD. RESULTS: Starting at three months of age, two groups of female transgenic mice carrying the "London" APP mutation (APP/V717I) were fed either, a standard diet (SD) composed of high carbohydrate/low fat chow, or a ketogenic diet (KD) composed of very low carbohydrate/high saturated fat chow for 43 days. Animals fed the KD exhibited greatly elevated serum ketone body levels, as measured by beta-hydroxybutyrate (3.85 +/- 2.6 mM), compared to SD fed animals (0.29 +/- 0.06 mM). In addition, animals fed the KD lost body weight (SD 22.2 +/- 0.6 g vs. KD 17.5 +/- 1.4 g, p = 0.0067). In contrast to earlier studies, the brief KD feeding regime significantly reduced total brain Abeta levels by approximately 25%. Despite changes in ketone levels, body weight, and Abeta levels, the KD diet did not alter behavioral measures. CONCLUSION: Previous studies have suggested that diets rich in cholesterol and saturated fats increased the deposition of Abeta and the risk of developing AD. Here we demonstrate that a diet rich in saturated fats and low in carbohydrates can actually reduce levels of Abeta. Therefore, dietary strategies aimed at reducing Abeta levels should take into account interactions of dietary components and the metabolic outcomes, in particular, levels of carbohydrates, total calories, and presence of ketone bodies should be considered.

Journal Article↗
PubMed1990

Extensive splenic B cell activation in IgM-transgenic mice.

Two lines of IgM-transgenic mice were analyzed for the state of activation of their splenic compartment, with regard to the frequency of large cells in the different lymphoid subpopulations, and to the isotype distribution of background plasma cells. We observed an extensive B cell activation preferentially involving B lymphocytes co-expressing transgenic and endogenous IgM (IgD), and resulting in massive immunoglobulin class switch. Nearly all splenic plasma cells contain endogenous immunoglobulins, with frequencies of IgG and IgA plasma cells significantly higher than in normal mice. There are virtually no plasma cells that produce only the transgenic IgM. Moreover, only a proportion of plasma cells producing endogenous immunoglobulins co-express the transgenic product. In addition to these observations that apply to both transgenic lines, differences were found between the two lines concerning the quantitative expression of the transgenic IgM, the frequency of cells expressing the transgene and the magnitude of switch. These data are indicative of the complexity of the IgM-transgenic mouse model, in which the phenomenology may depend on the transgene insertional position, on B cell physiology and on immunological mechanisms of recognition, induction and regulation.

Animals↗