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PubMed1993

A rheumatoid factor transgenic mouse model of autoantibody regulation.

To address whether B cells expressing a disease-associated autospecificity are regulated in normal mice, we have established a rheumatoid factor (RF) transgenic model of autoimmunity, using V genes derived from an IgA anti-IgG2a RF isolated from an autoimmune MRL/lpr mouse. As we wished to study induction of tolerance during B cell development, we cloned the VH gene into an IgM expression vector. The RF we chose binds only IgG2a of the 'a' allotype (IgG2a) but not IgG2ab allowing us to produce transgenic animals on IgHa and IgHb backgrounds, which either express or lack the self-antigen. Two transgenic lines were studied. Using mice which lack the self-antigen, we show by fluorescence activated cell sorting and hybridoma analysis that the H and L transgenes are expressed to the exclusion of endogenous genes in most splenic B cells. In spite of good allelic exclusion, transgenic mice which are genetically capable of expressing IgG2aa have reduced but significant (approximately 50 micrograms/ml) serum levels. Nonetheless, the frequency and numbers of transgene-expressing B cells in peripheral lymphoid organs of such mice which have the self-antigen are similar to those which lack it (IgHb mice). Thus, B cells expressing an anti-self IgG2a surface receptor can develop in this system. Whether such B cells are anergic or otherwise regulated in autoantigen-expressing mice is discussed.

Animals↗
PubMedDate not supplied

HLA and H2 class II transgenic mouse models to study susceptibility and protection in autoimmune thyroid disease.

Using single H2 and HLA class II transgenic mice, in the absence of endogenous H2 class II molecules, we have studied the permissiveness of class II molecules for experimental autoimmune thyroiditis (EAT). Resistant strains expressing susceptible class II molecules, H2Ak or HLA-DR3, developed EAT, clearly demonstrating the importance of class II gene inheritance. Polymorphism for HLA-DRB1 was observed, as DR3, but not DR2 or DR4, molecules were permissive for EAT induction with either mouse (m) or human (h) thyroglobulin (Tg). HLA-DQ polymorphism was also detectable, as hTg-induced EAT developed in DQ8+, but not DQ6+, mice. Class II gene interactions leading to reduced EAT severity were observed in H2 transgenic mice, when H2E transgene was expressed in H2A+ mice or H2A molecules were introduced into our novel H2A- E+ transgenic model. Similarly, in DR3+ mice, only the DQ8 transgene reduced EAT severity, depending on both background genes (C57BL/10 or NOD) and Tg species. Based on computer-predicted, class II-binding motifs, potential pathogenic Tg peptides, either unique to hTg (H2A- E+ model) or shared between mTg and hTg (HLA-DR3+ model), were identified. We have also developed a Graves' disease model by immunizing DR3+ mice with TSH receptor DNA. Thus, transgenic models are excellent tools to study human autoimmune thyroid diseases in the context of murine EAT.

Animals↗
PubMed2001

Transgenic mouse models of Alzheimer's disease: phenotype and mechanisms of pathogenesis.

A range of transgenic mice have been created to model Alzheimer's disease. These include mice expressing human forms of the amyloid precursor protein, the presenilins and, more recently, tau. Several of the models develop features of the disease including amyloid pathology, cholinergic deficits, neurodegeneration and cognitive impairment. Progress in the characterization and use of these model animals is discussed.

Alzheimer Disease↗
PubMed2001

Partial resistance to malonate-induced striatal cell death in transgenic mouse models of Huntington's disease is dependent on age and CAG repeat length.

Transgenic Huntington's disease (HD) mice, expressing exon 1 of the HD gene with an expanded CAG repeat, are totally resistant to striatal lesion induced by excessive NMDA receptor activation. We now show that striatal lesions induced by the mitochondrial toxin malonate are reduced by 70-80% in transgenic HD mice compared with wild-type littermate controls. This occurred in 6- and 12-week-old HD mice with 150 CAG repeats (line R6/2) and in 18-week-old, but not 6-week-old, HD mice with 115 CAG repeats (line R6/1). Therefore, we show for the first time that the resistance to neurotoxin in transgenic HD mice is dependent on both the CAG repeat length and the age of the mice. Importantly, most HD patients develop symptoms in adulthood and exhibit an inverse relationship between CAG repeat length and age of onset. Transgenic mice expressing a normal CAG repeat (18 CAG) were not resistant to malonate. Although endogenous glutamate release has been implicated in malonate-induced cell death, glutamate release from striatal synaptosomes was not decreased in HD mice. Malonate-induced striatal cell death was reduced by 50-60% in wild-type mice when they were treated with either the NMDA receptor antagonist MK-801 or the caspase inhibitor zVAD-fmk. These two compounds did not reduce lesion size in transgenic R6/1 mice. This might suggest that NMDA receptor- and caspase-mediated cell death pathways are inhibited and that the limited malonate-induced cell death still occurring in HD mice is independent of these pathways. There were no changes in striatal levels of the two anti cell death proteins Bcl-X(L) and X-linked inhibitor of apoptosis protein (XIAP), before or after the lesion in transgenic HD mice. We propose that mutant huntingtin causes a sublethal grade of metabolic stress which is CAG repeat length-dependent and results in up-regulation over time of cellular defense mechanisms against impaired energy metabolism and excitotoxicity.

Aging↗
PubMed2003

Pathobiology of autochthonous prostate cancer in a pre-clinical transgenic mouse model.

BACKGROUND: Animal models that closely mimic clinical disease can be exploited to hasten the pace of translational research. To this end, we have defined windows of opportunity in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model of prostate cancer as a paradigm for designing pre-clinical trials. METHODS: The incidence of cancer, metastasis, and distribution of pathology were examined as a function of time in TRAMP mice. The expression of various markers of differentiation were characterized. RESULTS: The TRAMP model develops progressive, multifocal, and heterogeneous disease. Each lobe of the prostate progressed at a different rate. Cytokeratin 8, E-cadherin, and androgen receptor (AR) were expressed during cancer progression but levels were reduced or absent in late stage disease. A distinct epithelial to neuroendocrine (ENT) shift was observed to be a stochastic event related to prostate cancer progression in TRAMP. CONCLUSIONS: This study will serve as the basis for the rational design of pre-clinical studies with genetically engineered mouse models.

Adenocarcinoma↗
PubMed2003

Transgenic mouse models of human CYP3A4 gene regulation.

CYP3A4, the predominant but variably expressed cytochrome P450 of adult human liver, is subject to multifaceted constitutive regulation as well as transcriptional induction by a variety of structurally unrelated xenobiotics. Using transient transfections in HepG2 cells, we previously demonstrated the existence of a potent xenobiotic-responsive enhancer module located between - 7.2 and - 7.8 kilobases upstream of the CYP3A4 transcription start site. Induction is mediated by interaction of transcription factor binding sites in the XREM with the nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR). To determine the in vivo relevance of these findings and to establish a mouse model of human CYP3A4 regulation, we have generated transgenic mice carrying constructs comprising the upstream regulatory region of the human CYP3A4 gene linked to the lacZ reporter gene. Constitutive expression was observed in a developmental, tissue- and cell-specific fashion that mirrors the human situation. In addition, robust hepatic and intestinal induction with a range of reagents known to activate PXR and/or CAR (e.g., dexamethasone, pregnenolone 16alpha-carbonitrile, and phenobarbital) was observed. However, no expression or induction was apparent with a construct lacking upstream sequences beyond - 3.2 kilobases. Histochemical staining for beta-galactosidase activity revealed that dose-dependent increases in transgene levels were associated with a zonal expansion of lacZ expressing hepatocytes, suggesting that xenobiotic induction of CYP3A genes operates primarily through the recruitment of more cells committed to expression. In summary, CYP3A4/lacZ transgenic mice provide an in vivo model for the study of the molecular mechanisms involved in the regulation of a significant human drug metabolizing enzyme.

Animals↗
PubMed2005

Striatal neuronal apoptosis is preferentially enhanced by NMDA receptor activation in YAC transgenic mouse model of Huntington disease.

Huntington disease (HD), caused by expansion >35 of a polyglutamine tract in huntingtin, results in degeneration of striatal medium spiny neurons (MSNs). Previous studies demonstrated mitochondrial dysfunction, altered intracellular calcium release, and enhanced NMDAR-mediated current and apoptosis in cellular and mouse models of HD. Here, we exposed cultured MSNs from YAC transgenic mice, expressing full-length human huntingtin with 18, 72, or 128 repeats, to a variety of apoptosis-inducing compounds that inhibit mitochondrial function or increase intracellular calcium, and assessed apoptosis 24 h later. All compounds produced a polyglutamine length-dependent increase in apoptosis, but NMDA produced the largest potentiation in apoptosis of YAC72 and YAC128 versus YAC18 MSNs. Moreover, reduction of NMDAR-mediated current and calcium influx in YAC72 MSNs to levels seen in wild-type reduced NMDAR-mediated apoptosis proportionately to wild-type levels. Our results suggest that increased NMDAR signaling plays a major role in enhanced excitotoxic MSN death in this HD mouse model.

Animals↗
PubMed2003

Amyloid-beta immunization in Alzheimer's disease transgenic mouse models and wildtype mice.

Alzheimer's disease is the most prevalent form of dementia worldwide. Therapies are desperately needed to prevent and cure the disease. Mouse models of amyloid-beta deposition [APP and PSAPP transgenic (tg) mice] have been useful in determining the role of amyloid-beta (A beta) in both the pathogenesis and cognitive changes in AD. In addition, they have allowed scientists to investigate potential AD therapies in living animals. Active and passive A beta immunizations have been employed successfully in APP and PSAPP tg mice to lower cerebral A beta levels and improve cognition. Optimization of immunization protocols and characterization of immune responses in wildtype mice have been reported. Based on the promising results of A beta immunization studies in mice, a clinical trial was initiated for A beta vaccination in humans with AD. Although no adverse effects were reported in the Phase I safety trials, about 5% of AD patients in the phase II clinical trial developed meningoencephalitis, ending the trial prematurely in March 2002. Studies in AD mouse models and wildtype mice may help elucidate the mechanism for these unwanted side effects and will be useful for testing newer, safer vaccines for future use in human clinical trials.

Alzheimer Disease↗
PubMed1995

A second generation transgenic mouse model expressing both hemoglobin S (HbS) and HbS-Antilles results in increased phenotypic severity.

We report on a second generation of transgenic mice produced by crossing a transgenic mouse line expressing high levels of human alpha and beta S chains (alpha H beta S [beta MDD]) with a line expressing human alpha and beta S-Antilles (beta SAnt). We hypothesized that mice expressing both hemoglobins (Hbs) would have a more severe phenotype because the reduced oxygen affinity and solubility of the beta S-Antilles might enhance the rate and extent of polymer formation. We obtained mice that expressed both beta S and beta S-Antilles. The doubly transgenic mice that are heterozygous for deletion of mouse beta Major (beta MD) occurred with reduced frequency and those that are homozygous for deletion of mouse beta Major (beta MDD) occurred at a much reduced frequency and suffered early mortality. Human alpha was 58% of all alpha globin for all animals, whereas beta S and beta S-Antilles were 34% and 28% of all beta globins for beta MD mice and 42% and 36% for beta MDD mice. Hematocrit, Hb, and mean corpuscular Hb were normal for all transgenic mice, but reticulocyte levels were higher for the doubly transgenic mice versus alpha H beta S [beta MDD] mice older than 30 days (10.0% +/- 1.0% v 4.3% +/- 0.4%; P < .001, mean +/- SE, n = 20 and n = 10, respectively) and control mice (3.9% +/- 0.4%). Reticulocytosis was more severe in mice less than 30 days old ( > 20% for alpha H beta S beta S-Ant[beta MDD] mice). The median mean corpuscular hemoglobin concentration of doubly transgenic mice was higher than that of alpha H beta S[beta MDD] mice with a variable number of very dense cells. Delay times for polymerization of Hb in red blood cells from alpha H beta S beta S-Ant[beta MDD] mice were shorter than those of alpha H beta S[beta MDD] mice, and there were fewer cells with delay times greater than 100 seconds. Urine-concentrating ability in control mice under ambient conditions is 2,846 +/- 294 mOsm and was reduced 30% to 1,958 +/- 240 mOsm, P < 4 x 10(-8) in all mice expressing both transgenes. We conclude that doubly transgenic mice have a more severe phenotype than either of the two parental lines. These mice may be suitable for validating therapeutic intervention in sickle cell disease.

Anemia, Sickle Cell↗
PubMed1993

Transgenic mouse models of lipoprotein metabolism and atherosclerosis.

Lipoprotein transport genes have either been added to the germ line of mice by transgenic techniques or knocked out by homologous recombination in embryonic stem cells. The resultant over- or underexpression of these genes has resulted in new insights about how these genes function in the body and their role in lipoprotein metabolism. Either singly or in combination, these genetic modifications can be used to engineer the mouse to make it a better model for human lipoprotein disorders and atherosclerosis.

Animals↗
PubMed1997

Behavioral reactivity to aversive stimuli in a transgenic mouse model of impaired glucocorticoid (type II) receptor function: effects of diazepam and FG-7142.

Transgenic mice with impaired type II-glucocorticoid receptor mediated feedback inhibition of hypthalamic-pituitary-adrenal activity were assessed in three different tests assessing behavioral reactivity to aversive stimuli, the elevated plus maze, the Thatcher-Britton novelty-conflict paradigm, and the startle paradigm. Transgenic mice more frequently entered and spent more time in the open arms of the elevated plus in comparison to B6C/3F1 mice. Transgenic mice took significantly longer to begin eating in the Thatcher-Britton novelty conflict paradigm, and displayed increased reactivity in the startle paradigm. Administration of 1 or 2 mg/kg diazepam reversed the behavioral effects observed in all three tests. Administration of the benzodiazepine receptor inverse agonist N-methyl-beta-carboline-3 carboxamide (FG-7142, 10 mg/kg) reduced the ratio of open to total arm entries and the time spent in the open arms of the plus maze in transgenic, but not B6C/3F1, mice. This dose of FG-7142 did not influence performance of either strain in the Thatcher-Britton or startle paradigms. These results are discussed in terms of the hypothesis that the transgenic mice are more sensitive to the aversive properties of novel stimuli, and that they may have difficulty discriminating between signals of relative safety and danger.

Animals↗
PubMed1997

Receptor editing in a transgenic mouse model: site, efficiency, and role in B cell tolerance and antibody diversification.

Mice carrying transgenic rearranged V region genes in their IgH and Igkappa loci to encode an autoreactive specificity direct the emerging autoreactive progenitors into a pre-B cell compartment, in which their receptors are edited by secondary Vkappa-Jkappa rearrangements and RS recombination. Editing is an efficient process, because the mutant mice generate normal numbers of B cells. In a similar nonautoreactive transgenic strain, neither a pre-B cell compartment nor receptor editing was seen. Thus, the pre-B cell compartment may have evolved to edit the receptors of autoreactive cells and later been generally exploited for efficient antibody diversification through the invention of the pre-B cell receptor, mimicking an autoreactive antibody to direct the bulk of the progenitors into that compartment.

Animals↗
PubMed2003

Transgenic mouse models for studies of the role of polyamines in normal, hypertrophic and neoplastic growth.

Transgenic mice expressing proteins altering polyamine levels in a tissue-specific manner have considerable promise for evaluation of the roles of polyamines in normal, hypertrophic and neoplastic growth. This short review summarizes the available transgenic models. Mice with large increases in ornithine decarboxylase (ODC), S-adenosylmethionine decarboxylase or antizyme, a protein regulating polyamine synthesis by reducing polyamine transport and ODC in the heart, have been produced using constructs in which the protein is expressed from the alpha -myosin heavy-chain promoter. These mice are useful in studies of the role of polyamines in hypertrophic growth. Expression from keratin promoters has been used to target increased synthesis of ODC, spermidine/spermine-N(1)-acetyltransferase (SSAT) and antizyme in the skin. Such expression of ODC leads to an increased sensitivity to chemical and UV carcinogenesis. Expression of antizyme inhibits carcinogenesis in skin and forestomach. Expression of SSAT increases the incidence of skin papillomas and their progression to carcinomas in response to a two-stage carcinogenesis protocol. These results establish the importance of polyamines in carcinogenesis and neoplastic growth and these transgenic mice will be valuable experimental tools to evaluate the importance of polyamines in mediating responses to oncogenes and studies of cancer chemoprevention.

Acetyltransferases↗
PubMed2001

L-selectin can facilitate metastasis to lymph nodes in a transgenic mouse model of carcinogenesis.

L-selectin mediates homing of lymphocytes to lymph nodes (LN). Transgenic mice that express rat insulin promoter regulated simian virus 40 Tag (RIP-Tag) develop large, local cancers that metastasize to liver but not LN. To test whether this lack of LN metastases reflects their absence from the circulation, transgenic mice were produced that express Tag (T), L-selectin (L), and Escherichia coli LacZ (Z), in pancreatic beta cells. LTZ mice developed insulinomas that specifically had LN metastases; metastasis was blocked by an anti L-selectin mAb. LacZ(+) tumor cells from these LN homed to secondary LN upon transfer. These results suggest that the highly vascularized islet carcinomas are shedding tumor cells into the bloodstream, which is a necessary but insufficient condition for metastasis to occur; L-selectin can facilitate homing of such tumor cells to LN, resulting in metastasis.

Animals↗
PubMedDate not supplied

Transgenic mouse models and germ cell transplantation: two excellent tools for the analysis of genes regulating male fertility.

This review presents new horizons for research opened by the combination of transgenic mouse technology and germ cell transplantation. Germ cell transfer allows to study defects causing subfertility or infertility in many mutant or transgenic mice. The successful culture, cryopreservation, and stable transfection of spermatogonial stem cells combined with the germ cell transplantation technique provide an alternative route for manipulation of the male germ line.

Animals↗
PubMed2005

Estrogen contributes to the onset, persistence, and malignant progression of cervical cancer in a human papillomavirus-transgenic mouse model.

Cervical cancer is a leading cause of death by cancer among women worldwide. High-risk human papillomaviruses (HPVs) are the major etiological agents for cervical cancer, but other factors likely contribute to cervical cancer, because these cancers commonly arise decades after initial exposure to HPV. Estrogen is thought to be one such cofactor; however, its temporal requirements in human cervical cancer are not known. Here we evaluate the temporal requirements of estrogen in cervical carcinogenesis in a mouse model for HPV-associated cervical cancer. Tumors arising in HPV16 transgenic mice treated with estrogen for 9 months were greatly increased in their size compared with tumors developing after 6 months of estrogen treatment. HPV16 transgenic mice treated 6 months with estrogen followed by 3 months without exogenous estrogen had significantly fewer tumors and the tumors were smaller and less aggressive than those arising in mice treated the full 9 months. Importantly, cervical cancers that arose in the mice treated the first 6 of 9 months with estrogen must have regressed, based upon the reduced incidence of cancers in these mice compared with those treated for 6 months with estrogen, then immediately analyzed. We conclude that estrogen plays a critical role not only in the genesis of cervical cancer but also in its persistence and continued development in this mouse model. These findings raise the clinically relevant possibility that, if human cervical cancer has a similar dependence on estrogen for continued tumor growth, then antiestrogen therapy may be effective in the treatment of cervical cancer.

Animals↗
PubMed2000

Vitamin E reduces chromosomal damage and inhibits hepatic tumor formation in a transgenic mouse model.

We have previously shown that chronic activation of mitogenic signaling induced by over-expression of c-myc and transforming growth factor-alpha (TGFalpha) transgenes in mouse liver induces a state of oxidative stress. We therefore proposed that increased reactive oxygen species (ROS) generation might be responsible for the extensive chromosomal damage and acceleration of hepatocarcinogenesis characteristic for TGFalpha/c-myc mice. In this study, we show that vitamin E (VE), a potent free radical scavenging antioxidant, is able to protect liver tissue against oxidative stress and suppress tumorigenic potential of c-myc oncogene. Dietary supplementation with VE, starting from weaning, decreased ROS generation coincident with a marked inhibition of hepatocyte proliferation while increasing the chromosomal as well as mtDNA stability in the liver. Similarly, dietary VE reduced liver dysplasia and increased viability of hepatocytes. At 6 mo of age, VE treatment decreased the incidence of adenomas by 65% and prevented malignant conversion. These results indicate that ROS generated by over-expression of c-myc and TGFalpha in the liver are the primary carcinogenic agents in this animal model. Furthermore, the data demonstrate that dietary supplementation of VE can effectively inhibit liver cancer development.

Animals↗