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PubMed2003

Mast cells in the kidney.

Mast cells have become a recent concern in the nephrological world. The development of antibodies to mast cell-specific enzymes, tryptase and chymase, has facilitated the study of mast cells in the kidney. Now, they are investigated immunohistochemically as well as histochemically. There are three types of human mast cells, MC(T), which contains exclusively tryptase, MC(TC), which has both tryptase and chymase, and MC(C), which contains only chymase. Many immunohistochemical studies involving mast cells have been conducted through the use of renal biopsy specimens. As a result, human renal diseases including various glomerulonephritis and pyelonephritis are found to have increased the number of mast cells in the renal cortex, especially in the area of fibrosis. The relationship between the number of mast cells and the prognosis of renal diseases has been proved to be significantly correlated in many reports. The subtypes of mast cells in these diseases are variably present, and no tendency of subtype specificity has been found. With the use of electron microscopically, mast cells are observed to be in contact with other interstitial cells or to infiltrate into tubules. Functionally, human renal mast cells resemble lung mast cells. Inhibitory substances for mast cell proliferation have been found in the mouse kidney. Compared with the results of human studies, mast cells are not found in the interstitum in animal models of renal diseases, except in a few transgenic mouse models and magnesium-deficient rats. Little is known about the exact roles that mast cells play in the renal interstitium. Future studies will hopefully make their characteristics clear.

Animals↗
PubMed1999

p53 tumor suppressor gene expression in the mouse ovary during an artificially induced ovulatory cycle.

OBJECTIVE: To evaluate the expression of p53 in the mouse ovary during an artificially induced ovulatory cycle. STUDY DESIGN: Ovulation induction was performed using pregnant mares' serum gonadotropin/human chorionic gonadotropin (PMSG/hCG). First, a p53 promoter-chloramphenicol acetyl transferase (CAT) transgenic mouse model was used. Protein samples from ovaries of transgenic mice were assayed for CAT activity as evidence of p53 promoter activation. Next, RNA extracted from CD-1 mouse ovaries was used for reverse transcription/polymerase chain reaction (PCR) and northern blot analysis using a p53-specific probe. RESULTS: Increased CAT activity was noted in transgenic mice treated with PMSG/hCG as compared with controls. PCR studies on transgenic mice using primers for CAT and on CD-1 mice using primers for wild type p53 substantiated this observation. Furthermore, CAT assay and northern analysis, performed on samples obtained at serial time intervals from induction, indicated that maximal p53 expression occurs around the time of ovulation, beginning 48 hours after PMSG and peaking 6-12 hours after hCG administration. CONCLUSION: The temporal expression of p53 in the ovary during a PMSG/hCG artificially induced ovulatory cycle may indicate a role for p53 in processes of differentiation of granulosa cells into luteal cells.

Animals↗
PubMed2006

IL-12 overexpression in mice as a model for Sjögren lung disease.

Interleukin-12 (IL-12), a Th1 proinflammatory cytokine, is reported to be increased in Sjögren syndrome. To evaluate the effects of local Th1/Th2 deregulation, we generated a transgenic mouse model that overexpresses IL-12 in the lungs. IL-12 transgenic mice developed bronchial and alveolar abnormalities strikingly similar to those found in the lungs of Sjögren patients. Pathologically, lung abnormalities began at approximately 4 mo of age and were characterized by lymphocytic infiltrates around the bronchi, intraluminal periodic acid Schiff-positive debris, increased cell proliferation in the alveolar region, and increased interstitial and alveolar macrophages. Functionally, these abnormalities translated into decreased mucociliary clearance (P<0.05 vs. wild-type littermates) and increased oxidative stress (P<0.01). The pathological and functional abnormalities were accompanied by significant changes in lung natural killer (NK) cells. The number of NK cells was fourfold higher in IL-12 transgenic than wild-type lungs (20% of all lymphoid cells vs. 5%) during the first month of life. NK cells then decreased within a narrow window of time (from 30 to 50 days of age), reaching a nadir of approximately 2% on day 50, and remained at these low levels thereafter. This new mouse model highlights the role of IL-12 in the initiation of Sjögren syndrome.

Animals↗
PubMed2005

Mouse models of human neurodegenerative disorders: requirements for medication development.

Central nervous system diseases constitute a major target for drug development. Transgenic mouse models, in which genes identified in familial forms of human brain diseases are expressed in mouse neurons and glia, offer opportunities to detect and follow pathologic progression and provide potential biomarkers by which to assess therapeutic interventions. Evidence for Alzheimer disease suggests some starting requirements for the experimental data that could enhance the likelihood of developing medications in these mouse models that would also be effective in humans.

Alzheimer Disease↗
PubMed1998

Longitudinal cohort analysis of lethal prostate cancer progression in transgenic mice.

PURPOSE: Human prostate cancer is variably lethal, shows heterogeneous progression, and exhibits a spectrum of histopathology. Traditional rodent models of prostate cancer lack these characteristics. An alternative, autochthonous model of prostate cancer consists of transgenic mice which develop prostate cancer due to prostatic expression of SV40 T antigen. Lethal progression of such cancers in individual mice has not been previously characterized. Studies were undertaken to characterize the longitudinal progression of prostate cancers in these transgenic mice. METHODS: A prospective longitudinal cohort study was undertaken to characterize prostate cancer volume, progression, lethality, and histological heterogeneity in a transgenic mouse model of prostatic adenocarcinoma. Fifty-one transgenic mice were followed prospectively to determine the age at onset of palpable tumor and age at cancer-related death. Tumor volume was followed longitudinally by magnetic resonance imaging (MRI) in a subset of these mice and lethal cancers were evaluated by histopathology. RESULTS: Primary tumors became palpable at 10-38 weeks of age. Palpable tumors always preceded lethal progression. Cancer death followed 2-9 weeks later, and age at cancer death varied from 24 to 39 weeks of age. The histopathological changes were heterogeneous. Primary tumors were detectable by MRI before they became detectable by palpation. MRI showed that, analogous to human prostate cancers, volume of early stage primary tumors did not necessarily predict age at cancer death. CONCLUSION: Prostate cancer in transgenic mice mimics heterogeneic tumor progression in human prostate cancer, providing a uniquely relevant pre-clinical model. Tumor detection by MRI and palpation are valid surrogate measures of tumor progression in this model.

Animals↗
PubMed1998

Expression of a fusion gene consisting of the mouse growth hormone-releasing hormone gene promoter linked to the SV40 T-antigen gene in transgenic mice.

Limited information is available concerning the regulation of growth hormone-releasing hormone (GHRH) gene expression in the hypothalamus, largely because of the lack of a suitable cellular model. In an attempt to immortalize hypothalamic GHRH-producing neurons, we have generated a transgenic mouse model which expresses the simian virus 40 (SV40) T-antigen gene (Tag) under the control of the GHRH gene promoter. The transgene contains approximately 5 kb of mouse GHRH gene sequences, including 3.5 kb of the 5'-flanking region, the entire hypothalamic exon 1 and 1.5 kb of intron 1, fused to the SV40 Tag gene. This construct was microinjected into fertilized oocytes. Fourteen of 96 mice born had integrated the transgene. These mice were fertile and showed no signs of central or peripheral tumors. The pattern of expression of the SV40 Tag gene was analyzed in four different transgenic lines by RT-PCR. The tissues tested include: hypothalamus, pituitary, cortex, cerebellum, spinal cord, adrenal, testis, spleen and lung. Transgene expression was consistently detected in the hypothalamus of all lines. In addition, SV40 Tag expression was also detected in the hypothalamus by Northern blot analysis in two of the transgenic lines. SV40 Tag expression was also detected in the testis of all transgenic lines by RT-PCR. This result was not expected since the GHRH gene sequences present in the transgene do not include the testis-specific transcription initiation site previously described. This suggests that GHRH gene expression in the mouse testis can be directed by regulatory sequences located downstream of the testis specific transcription start site. We conclude that the promoter region of the GHRH gene included in this construct contains the regulatory elements necessary to drive hypothalamic and testis expression in vivo. In addition, all mice from one of the transgenic lines developed cataracts in both eyes. SV40 Tag expression was detected not only in eyes with cataracts, but also, to a lesser extent, in eyes from other transgenic lines. Furthermore, the endogenous GHRH gene was found to be expressed in the eyes of normal mice.

Animals↗
PubMedDate not supplied

Learning and memory in transgenic mice modeling Alzheimer's disease.

Recent advances in behavioral analyses of transgenic mouse models of Alzheimer's disease (AD) are discussed, and their impact on our understanding of the molecular basis of cognitive impairment in AD is considered. Studies of the relationship between memory and A Beta in transgenic mice expressing the amyloid precursor protein (APP) and its variants suggest that aging promotes the formation of soluble A Beta assemblies mediating negative effects on memory. A significant component of memory loss in APP transgenic mice is apparently caused by soluble A Beta assemblies, but whether and how much of the dementia within individuals afflicted with AD is caused by these A Beta species is unclear. Future studies in composite transgenic mice developing amyloid plaques, neurofibrillary tangles, and other AD pathology may allow for the determination of the relative contribution of A Beta and non-A Beta components to dementia.

Alzheimer Disease↗
PubMed2001

Animal models of rheumatoid arthritis.

Animal models of arthritis are used to study pathogenesis of disease and to evaluate potential anti-arthritic drugs for clinical use. Therefore morphological similarities to human disease and capacity of the model to predict efficacy in humans are important criteria in model selection. Animal models of rheumatoid arthritis (RA) with a proven track record of predictability for efficacy in humans include: rat adjuvant arthritis, rat type II collagen arthritis, mouse type II collagen arthritis and antigen-induced arthritis in several species. Agents currently in clinical use (or trials) that are active in these models include: corticosteroids, methotrexate, nonsteroidal anti-inflammatory drugs, cyclosporin A, leflunomide interleukin-1 receptor antagonist (IL-1ra) and soluble TNF receptors. For some of these agents, the models also predict that toxicities seen at higher doses for prolonged dosing periods would preclude dosing in humans at levels that might provide disease modifying effects. Data, conduct and features of the various models of these commonly utilized models of RA as well as some transgenic mouse models and less commonly utilized rodent models will be discussed with emphasis on their similarities to human disease.

Journal Article↗
PubMed1998

Altered expression of transforming growth factor betas during urethral and bulbourethral gland tumor progression in transgenic mice carrying the androgen-responsive C3(1) 5' flanking region fused to SV40 large T antigen.

We demonstrate that targeted expression of SV40 large T antigen (TAg) to the urethral (periurethral) and bulbourethral gland epithelium leads to adenocarcinoma formation in these tissues after 7 months of age, which are extremely rare sites for spontaneous tumor formation in humans. The development of proliferative lesions in the urethral gland predictably follows a temporal course of progression with approximately one third of male animals developing urethral tumors by 1 year of age. Tumor progression in these organs correlates to the level of TAg and p53 expression. Immunoprecipitation confirmed that SV40 TAg protein was bound to p53 and Rb p110 in vivo. Expression of transforming growth factor beta (TGFbetas) was evaluated during tumor progression of urethral gland carcinomas. Elevations of intracellular and extracellular TGFbeta1 and extracellular TGFbeta3 were found in preneoplastic and neoplastic lesions, suggesting that increased TGFbetas may augment tumor growth. c-Met expression showed a tendency for increased expression in the urethral gland carcinomas. We speculate that the directed expression of SV40 TAg by the hormone responsive C3(1) gene and subsequent tumor formation in these organs is influenced by androgens, since these tissues and carcinomas express androgen receptor (AR) and arise only in male transgenic mice. Several cell lines established from the urethral carcinomas were also shown to express AR, but are not androgen dependent in culture. To our knowledge, this is the first transgenic animal model for urethral and bulbourethral carcinomas. This transgenic mouse model and the cell lines derived from it may provide a unique opportunity for dissecting molecular mechanisms involved in the tumorigenesis of these organs which otherwise rarely develop cancer.

Aging↗
PubMedDate not supplied

Muscle-specific overexpression of human lipoprotein lipase in mice causes increased intracellular free fatty acids and induction of peroxisomal enzymes.

A transgenic mouse model for peroxisomal and mitochondrial induction caused by increased uptake of fatty acids in muscle was established. Transgenic mouse lines were generated using a human lipoprotein lipase (LPL) mini gene (3-20 copies) driven by the promoter of the muscle creatine kinase gene. Expression of human LPL was only observed in skeletal and cardiac muscle. In proportion to the level of LPL overexpression increased LPL activity in skeletal (up to 24-fold) and cardiac (up to three-fold) muscle, decreased plasma triglyceride levels, elevated free fatty acid (FFA) uptake by muscle tissue, weight loss (due to a reduction in muscle mass as well as adipose tissue mass) and premature death were observed. A remarkable increase in the number of mitochondria and peroxisomes was detected using oxide-electron microscopy. Proliferation of mitochondria and peroxisomes was confirmed by a dose-dependent increase of marker enzyme activity (succinate-dehydrogenase and catalase). In addition, peroxisomal acyl-CoAse enzyme protein was markedly elevated whereas mRNA was increased only up to two-fold. No changes in peroxisomal proliferator activated receptor alpha mRNA was found. This degree of proliferation and enzyme activity of mitochondria and peroxisomes suggests that FFA play an important role in the induction of these organelles. In addition, myopathy characterized by excessive glycogen storage, muscle fiber degeneration, and fiber atrophy with centralization of nuclei, mimicking several forms of human myopathies was noted. Our results imply that improper regulation of muscle LPL leading to increased fatty acid levels in muscle can cause severe pathological changes. This effect may be important in the pathogenesis of human myopathies. We conclude that these transgenic mouse lines could serve as a useful animal model for the investigation of myopathies and the effects of fatty acids on the induction of mitochondria and peroxisomes.

Animals↗
PubMed2004

Airway remodeling: lessons from animal models.

Airway remodeling, an array of persistent tissue structural changes that occurs through a process of injury and dysregulated repair linked to airway chronic inflammation, is presently believed to largely account for the disease mechanisms of asthma. Increases in airway smooth muscle mass are probably the main mechanism causing airway hyperresponsiveness, and changes in the extracellular matrix may stimulate smooth muscle growth and contribute to the mechanics of airway obstruction. The various components of airway remodeling described inhuman asthma have been successfully reproduced in animal models of several species. Most of the data have been contributed by rat models of allergic sensitization and repeated challenge,transgenic mouse models of cytokine overexpression localized to the lung and, more recently, allergen-driven mouse models using wild-type inbred strains. Overall, animal model shave provided significant insights into the mechanisms of airway remodeling and recent technological developments allow us to exploit these models in new directions. However, the challenge of finding new therapeutic strategies that prevent or control airway remodeling,thus providing etiopathogenically oriented treatments for asthma, still stands. Experimental airway remodeling in animals should be an essential tool for treatment discovery in the near future.

Animals↗
PubMed2000

Chronic hypersecretion of luteinizing hormone in transgenic mice disrupts both ovarian and pituitary function, with some effects modified by the genetic background.

When the pituitary or hypothalamus becomes resistant to steroid negative feedback, a vicious cycle ensues, resulting in chronic hypersecretion of luteinizing hormone (LH) from the pituitary and steroids from the ovaries. In women, LH hypersecretion is implicated in infertility, miscarriages, and development of granulosa cell tumors. Progress in defining the underlying mechanisms of LH toxicity, however, has been limited by the lack of well-defined animal models. To that end, we have developed a new transgenic mouse model (alpha-LHbetaCTP) wherein LH hypersecretion occurs chronically and results in several dire pathological outcomes. Chronic hypersecretion of LH was achieved by introducing a transgene containing a bovine alpha subunit promoter fused to the coding region of a chimeric LHbeta subunit. The alpha subunit promoter directs transgene expression only to gonadotropes. The LHbeta chimera contains the carboxyl-terminal peptide (CTP) of the human chorionic gonadotropin beta subunit linked to the carboxyl terminus of bovine LHbeta. This carboxyl extension extends the half-life of LH heterodimers that contain the chimeric beta subunit. In intact alpha-LHbetaCTP females, serum LH is elevated five- to ten-fold in comparison to nontransgenic littermates. Levels of testosterone (T) and estradiol (E2) also are elevated, with an overall increase in the T-to-E2 ratio. These transgenic females enter puberty precociously but are anovulatory and display a prolonged luteal phase. Anovulation reflects the absence of gonadotropin-releasing hormone (GnRH) and the inability to produce a pre-ovulatory surge of LH. The ovaries are enlarged, with reduced numbers of primordial follicles and numerous, giant, hemorrhagic follicles. Despite the pathological appearance of the ovary, females can be superovulated and mated. Although pregnancy occurs, implantation is compromised due to defects in uterine receptivity. In addition, pregnancy fails at midgestation, reflecting a maternal defect presumably due to estrogen toxicity. When the transgene is in a CF-1 background, all females develop granulosa cell tumors and pituitary hyperplasia by five months of age. They die shortly thereafter due to bladder atony and subsequent kidney failure. When the transgene is placed in other strains of mice, their ovaries develop a luteoma rather than a granulosa cell tumor and the pituitary develops pituitary hyperplasia followed by adenoma. In summary, alpha-LHbetaCTP mice provide a direct association between abnormal secretion of LH and development of a number of ovarian and pituitary pathological responses.

Adenoma↗
PubMed2005

Effects of pleiotrophin (PTN) over-expression on mouse long bone development, fracture healing and bone repair.

Pleiotrophin (PTN) was found to have potent effects on regulation of osteoblast recruitment, proliferation and differentiation. The present study examined the long-term effects of targeted PTN over-expression on bone development and repair in a transgenic mouse model. Femurs and tibiae from the PTN transgenic mice and the wild type mice at age 1, 2, 4, 6, 12 and 24 months were collected, and examined by radiography, peripheral quantitative computed tomography (pQCT), histology and mechanical testing. Age-matched PTN and the control mice received a standardized femoral fracture, followed by regular x-rays and sacrificed at day 16 post-fracture for histology examination. A cortical hole was drilled on the tibiae of age-matched PTN and wild type mice, collagen sponge with either saline, 100 ng of rhBMP-2 or rhPTN was implanted in the holes, and animals were sacrificed 10 days later, subject to pQCT and histology examinations. During early stages of bone development, the PTN mice had advanced bone growth in length and maturation, but the difference diminished in later life. The fracture healing was impaired in the PTN mice, and there was delayed callus formation and remodelling. The cortical holes treated with BMP-2 in the PTN mice had significantly less trabecular bone formation. The current study confirmed that the targeted PTN over-expression in mouse bone has moderate enhancing effects on early bone development; but the bones become brittle in later life. Fracture healing was impaired in the adult PTN mice and this may be due to inhibitory effects of PTN over-expression on BMP-2 mediated bone induction.

Animals↗
PubMed2005

Permanent genetic tagging of podocytes: fate of injured podocytes in a mouse model of glomerular sclerosis.

Injured podocytes lose differentiation markers. Therefore, the true identity of severely injured podocytes remains unverified. A transgenic mouse model equipped with a podocyte-selective injury induction system was established. After induction of podocyte injury, mice rapidly developed glomerulosclerosis, with downregulation of podocyte marker proteins. Proliferating epithelial cells accumulated within Bowman's space, as seen in collapsing glomerulosclerosis. In this study, the fate of injured podocytes was pursued. Utilizing Cre-loxP recombination, the podocyte lineage was genetically labeled with lacZ in an irreversible manner. After podocyte injury, the number of lacZ-labeled cells, which were often negative for synaptopodin, progressively declined, correlating with glomerular damage. Parietal epithelial cells, but not lacZ-labeled podocytes, avidly proliferated. The cells proliferating within Bowman's capsule and, occasionally, on the outer surface of the glomerular basement membrane were lacZ-negative. Thus, when podocytes are severely injured, proliferating parietal epithelial cells migrate onto the visceral site, thereby mimicking proliferating podocytes.

Animals↗
PubMed1994

Molecular dissection of multi-stage tumorigenesis in transgenic mice.

The epidemiology of cancer in humans and in animal models suggests that multiple genetic events are responsible for the genesis of malignant tumors. During development of many tumors, distinctive changes can be recognized: normal unaffected tissue, hyperplasia with a high incidence of proliferating cells, induction of tumor angiogenesis with the new growth of capillaries, solid tumors (neoplasia), and finally metastasis. The molecular analysis of tumorigenesis is often hampered by the unavailability of tissue specimens from the multiple stages. For this reason, the genetic reproducibility and the accessibility of tissue specimens have made transgenic mice a valuable tool to study the molecular events that are involved in the stepwise progression to the tumor phenotype. Many transgenic mouse models of human cancer, for example mammary epithelia, skin and liver, exhibit similar patterns of stepwise tumor development. In this review we discuss possible strategies to investigate the molecular events that are involved in multi-stage tumor development. Then we present in some detail the molecular dissection of tumor development in two transgenic models of fibrosarcomas of the skin, and a third transgenic mouse line that develops tumors of the beta cells in the islets of Langerhans (insulinomas). In particular, approaches to the molecular characterization of tumor cell proliferation and tumor angiogenesis are discussed.

Animals↗
PubMed1999

Cerebellar allografts survive and transiently alleviate ataxia in a transgenic model of spinocerebellar ataxia type-1.

Spinocerebellar ataxia type 1 (SCA-1) is one of several neurodegenerative diseases, including Huntington's disease, spinobulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, and SCA-2, SCA-3, SCA-6, and SCA-7, each caused by an expanded number of CAG repeats in the coding region of their respective genes. The mechanism by which the resulting proteins are pathogenic is unknown. Clinical trials of neural transplants in Huntington's disease patients are under way. While initial reports are encouraging, definitive evidence of graft survival in patients despite the ongoing disease process is not possible with current imaging techniques. Transplants in primates have shown long-term survival of striatal grafts and recovery of function, but have used lesioning to model Huntington's phenotypically. Studies of striatal grafts in a transgenic mouse model of Huntington's have not yet shown a behavioral benefit. We describe a behavioral benefit of cerebellar grafts in a transgenic model of SCA-1 in which the ataxic phenotype results from expression of an expanded ataxin-1 protein. Mice were transplanted at an age when their ataxic phenotype is just becoming evident. Compared with sham-operated littermates, grafted mice showed better performance on multiple behavioral tests of cerebellar function. Differences persisted for 10 to 12 weeks posttransplant, after which there was a progressive decline in motor performance. At 20 weeks postsurgery, donor Purkinje cell survival was evident in 9 of 12 graft recipients. These results indicate that transplants can have behavioral benefits and grafts can survive long-term despite the ongoing pathological process in a brain actively expressing an expanded polyglutamine protein.

Animals↗
PubMed2004

Transgenic mice as an in vivo model of lymphomagenesis.

This review covers multiple data obtained on genetically modified mice that help to elucidate various intricate molecular mechanisms of lymphomagenesis in humans. We are in a "golden age" of mouse genetics. The mouse is by far the most accessible mammalian system physiologically similar to humans. Transgenic mouse models have illuminated how different genes contribute to human lymphomagenesis. Multiple experiments with transgenic mice have not only confirmed the data obtained for human lymphomas but also gave additional evidence for the role of some genes and cooperative participation of their products in the development of human lymphomas. Genes and gene networks detected on transgenic mice can successfully serve as molecular targets for tumor therapy. This review demonstrates the extraordinary possibilities of transgenic technology, which is presently one of the readily available, efficient, and accurate tools to solve the problem of cancer.

Animals↗
PubMed2001

Behavioural profiling of a murine Charcot-Marie-Tooth disease type 1A model.

Different features of motor behaviour were studied on a transgenic mouse model of Charcot-Marie-Tooth's disease (CMT). Mutants with 4 or 7 copies of the human PMP22 gene leading to a phenotype significantly close to CMT's disease type 1A were compared with control animals. The aim of the study was to validate this transgenic model and to characterise the impairments occurring in the various lines. Three main types of analysis were performed in 2-month-old mice without any peculiar visible deficit: (i) a study of standardised clinical tests (SHIRPA protocol) demonstrated that only a few motor deficits were expressed; (ii) a measurement of general spontaneous activity by means of a commercial video-tracking system was performed and revealed that the main spontaneous activities were identical in the three lines with, however, some slight localised modifications; and, (iii) by contrast, the three lines respond very differently to the footprints, grip strength, splay test and rotarod test. Even in lines with a significantly limited copy number of the transgene, we observed and quantified impairments. In conclusion, mutants of CMT1A seem to be a very pertinent model of this human pathology and will certainly be useful for therapeutic procedures and for theoretical studies on this disease.

Animals↗