Transgenic animals modelling polyamine metabolism-related diseases

Cloning of genes related to polyamine metabolism has enabled the generation of genetically modified mice and rats overproducing or devoid of proteins encoded by these genes. Our first transgenic mice overexpressing ODC (ornithine decarboxylase) were generated in 1991 and, thereafter, most genes involved in polyamine metabolism have been used for overproduction of the respective proteins, either ubiquitously or in a tissue-specific fashion in transgenic animals. Phenotypic characterization of these animals has revealed a multitude of changes, many of which could not have been predicted based on the previous knowledge of the polyamine requirements and functions. Animals that overexpress the genes encoding the inducible key enzymes of biosynthesis and catabolism, ODC and SSAT (spermidine/spermine N1-acetyltransferase) respectively, appear to possess the most pleiotropic phenotypes. Mice overexpressing ODC have particularly been used as cancer research models. Transgenic mice and rats with enhanced polyamine catabolism have revealed an association of rapidly depleted polyamine pools and accelerated metabolic cycle with development of acute pancreatitis and a fatless phenotype respectively. The latter phenotype with improved glucose tolerance and insulin sensitivity is useful in uncovering the mechanisms that lead to the opposite phenotype in humans, Type 2 diabetes. Disruption of the ODC or AdoMetDC [AdoMet (S-adenosylmethionine) decarboxylase] gene is not compatible with mouse embryogenesis, whereas mice with a disrupted SSAT gene are viable and show no harmful phenotypic changes, except insulin resistance at a late age. Ultimately, the mice with genetically altered polyamine metabolism can be used to develop targeted means to treat human disease conditions that they relevantly model.

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Drosophila brachyenteron regulates gene activity and morphogenesis in the gut

Development ◽

10.1242/dev.122.12.3707 ◽

1996 ◽

Vol 122 (12) ◽

pp. 3707-3718 ◽

Cited By ~ 14

Author(s):

J.B. Singer ◽

R. Harbecke ◽

T. Kusch ◽

R. Reuter ◽

J.A. Lengyel

Keyword(s):

Genetic Locus ◽

Malpighian Tubules ◽

Gene Activity ◽

Phenotypic Characterization ◽

Gut Development ◽

Allelic Series ◽

Genes Encoding

Chromosomal region 68D/E is required for various aspects of Drosophila gut development; within this region maps the Brachyury homolog T-related gene (Trg), DNA of which rescues the hindgut defects of deficiency 68D/E. From a screen of 13,000 mutagenized chromosomes we identified six non-complementing alleles that are lethal over deficiencies of 68D/E and show a hindgut phenotype. These mutations constitute an allelic series and are all rescued to viability by a Trg transgene. We have named the mutant alleles and the genetic locus they define brachyenteron (byn); phenotypic characterization of the strongest alleles allows determination of the role of byn in embryogenesis. byn expression is activated by tailless, but byn does not regulate itself. byn expression in the hindgut and anal pad primordia is required for the regulation of genes encoding transcription factors (even-skipped, engrailed, caudal, AbdominalB and orthopedia) and cell signaling molecules (wingless and decapentaplegic). In byn mutant embryos, the defective program of gene activity in these primordia is followed by apoptosis (initiated by reaper expression and completed by macrophage engulfment), resulting in severely reduced hindgut and anal pads. Although byn is not expressed in the midgut or the Malpighian tubules, it is required for the formation of midgut constrictions and for the elongation of the Malpighian tubules.

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Genetic and phenotypic characterization of sylvatic dengue virus type 2 strains

Virology ◽

10.1016/j.virol.2008.04.044 ◽

2008 ◽

Vol 377 (2) ◽

pp. 296-307 ◽

Cited By ~ 36

Author(s):

Nikos Vasilakis ◽

Eric B. Fokam ◽

Christopher T. Hanson ◽

Ethan Weinberg ◽

Amadou A. Sall ◽

...

Keyword(s):

Dengue Virus ◽

Virus Type ◽

Phenotypic Characterization ◽

Dengue Virus Type 2

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Isolation and Phenotypic Characterization of Human Adenovirus Type 2 Temperature-Sensitive Mutants

Journal of General Virology ◽

10.1099/0022-1317-41-2-303 ◽

1978 ◽

Vol 41 (2) ◽

pp. 303-314 ◽

Cited By ~ 24

Author(s):

G. R. Martin ◽

R. Warocquier ◽

C. Cousin ◽

J.-C. D'Halluin ◽

P. A. Boulanger

Keyword(s):

Human Adenovirus ◽

Adenovirus Type ◽

Phenotypic Characterization ◽

Temperature Sensitive ◽

Temperature Sensitive Mutants ◽

Adenovirus Type 2

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Genetic Analysis of Adenovirus Type 2 II. Preliminary Phenotypic Characterization of Temperature-Sensitive Mutants

Journal of Virology ◽

10.1128/jvi.15.5.1049-1056.1975 ◽

1975 ◽

Vol 15 (5) ◽

pp. 1049-1056 ◽

Cited By ~ 15

Author(s):

J. Weber ◽

M. Begin ◽

G. Khittoo

Keyword(s):

Genetic Analysis ◽

Adenovirus Type ◽

Phenotypic Characterization ◽

Temperature Sensitive ◽

Temperature Sensitive Mutants ◽

Adenovirus Type 2

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Kill two birds with one stone: making multi-transgenic pre-diabetes mouse models through insulin resistance and pancreatic apoptosis pathogenesis

10.7287/peerj.preprints.3437v1 ◽

2017 ◽

Author(s):

Siyuan Kong ◽

Jinxue Ruan ◽

Kaiyi Zhang ◽

Bingjun Hu ◽

Yuzhu Cheng ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Transgenic Mice ◽

Mouse Models ◽

Early Stage ◽

Transgenic Animals ◽

High Fat ◽

Adipose Tissues ◽

High Sucrose

Background. Type 2 diabetes, a chronic disease to which susceptibility is hereditary, is characterized by insulin resistance accompanied by defective insulin secretion. Mouse models, especially transgenic mice, play an important role in medical research. However, the transgenic mouse models that have been used in diabetes research are involved with single transgenes, focusing on the insulin gene or its mutants. Thus they mainly provide information related to Type 1 diabetes. Methods. Here, we attempted to focus comprehensively on genes related to pancreatic islet damage, peripheral insulin resistance and related environmental inducing factors by generating single-transgenic mice (CHOP), dual-transgenic mice (hIAPP-CHOP) and triple-transgenic mice (11β-HSD1-hIAPP-CHOP). The latter two types of transgenic animals were induced with high-fat, high-sucrose diets (HFHSD). We evaluated and analyzed the diabetes-related symptoms and the histopathological and immunohistochemical features of the transgenic animals. Results. Specifically, in the triple-transgene animals, the results of intraperitoneal glucose tolerance tests (IPGTT) began to change 60 days after induction (p<0.001). After 190 days of induction, the body weights (p<0.01) and plasma glucose levels of the animals in the Tg group were higher than those of the animals in the Nc group. After the mice were sacrificed, large amounts of lipid were found deposited in the adipose tissues (p<0.01) and ectopically deposited in the non-adipose tissues (p<0.05 or 0.01) of the animals in the Tg HFHSD group. The weights of the kidneys and hearts of the Tg animals were significantly increased (p<0.01). Serum C-P was decreased due to transgene effects, and insulin levels were increased due to the effects of the high-fat high-sucrose diet in the Tg HFHSD group, indicating that damaged insulin secretion and insulin resistance hyperinsulinemia existed simultaneously in these animals. The serum corticosterone levels of the animals in the Tg group were slightly higher than those of the Nc animals due to the effects of the 11βHSD-1 transgene and obesity. In the Tg HFHSD group, hepatic adipose deposition was more severe and the pancreatic islet area was enlarged under compensation, accompanying apoptosis. In the Tg ControlD group, hepatic adipose deposition was also severe, pancreatic islets were damaged, and their areas were decreased (p<0.05), and apoptosis of pancreatic cells occurred. Taken together, these data show that the transgenes led to early-stage pathological changes characteristic of type 2 diabetes in the triple-transgene HFHSD group. The disease of triple-transgenic mice was more severe than that of dual or single-transgenic mice. Conclusion. The use of multi-transgenes involved in insulin resistance and pancreatic apoptosis is a better way to generate polygene-related early-stage diabetes models.

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Impaired pericyte recruitment and abnormal retinal angiogenesis as a result of angiopoietin-2 overexpression

Thrombosis and Haemostasis ◽

10.1160/th06-05-0277 ◽

2007 ◽

Vol 97 (01) ◽

pp. 99-108 ◽

Cited By ~ 74

Author(s):

Yuxi Feng ◽

Franziska vom Hagen ◽

Frederick Pfister ◽

Snezana Djokic ◽

Sigrid Hoffmann ◽

...

Keyword(s):

Transgenic Mice ◽

Transgenic Animals ◽

Mouse Retina ◽

Vascular Density ◽

Wild Type ◽

Transgenic Mouse Line ◽

Oxygen Induced Retinopathy ◽

Genes Encoding ◽

Angiopoietin 2 ◽

The Impact

SummaryAngiopoietin-2 (Ang2) is among the relevant growth factors induced by hypoxia and plays an important role in the initiation of retinal neovascularizations. Ang2 is also involved in incipient diabetic retinopathy, as it may cause pericyte loss. To investigate the impact of Ang2 on developmental and hypoxia-induced angiogenesis, we used a transgenic mouse line overexpressing human Ang2 in the mouse retina. Transgenic mice displayed a reduced coverage of capillaries with pericytes (-14 %; p<0.01) and a 46% increase of vascular density of the capillary network at postnatal day 10 compared to wild type mice. In the model of oxygen-induced retinopathy (OIR), Ang2 overexpression resulted in enhanced preretinal (+103%) and intraretinal neovascularization (+29%). Newly formed intraretinal vessels in OIR were also pericyte-deficient (-26 %; p<0.01). The total expression of Ang2 in transgenic mice was seven-fold, compared with wild type controls. Ang2 modulated expression of genes encoding VEGF (+65%) and Ang1 (+79%) in transgenic animals. These data suggest that Ang2 is involved in pericyte recruitment, and modulates intraretinal, and preretinal vessel formation in the eye under physiological and pathological conditions.

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Genetic Interactions between the Coagulation and Fibrinolytic Systems

Thrombosis and Haemostasis ◽

10.1055/s-0037-1616209 ◽

2001 ◽

Vol 86 (07) ◽

pp. 130-137 ◽

Cited By ~ 13

Author(s):

Jay Degen

Keyword(s):

Associated Factors ◽

Genetic Interactions ◽

Phenotypic Characterization ◽

System Components ◽

Genes Encoding ◽

Hemostatic Factors ◽

Mouse Lines ◽

Made In

SummaryNearly all of the genes encoding the established coagulation and fibrinolytic factors have been successfully altered or disrupted in transgenic mice. Although comprehensive studies of each of these genetargeted mouse lines are still ongoing, the initial findings have significantly refined our understanding of the roles of selected hemostatic factors in vivo, and occasionally altered long-standing concepts. This review summarizes some of the progress that has been made in the generation and phenotypic characterization of mice lacking key hemostatic factors, including coagulation, fibrinolytic, platelet and endothelial cell-associated factors. New insights regarding the role(s) and interplay of hemostatic factors that have emerged from detailed studies of mice carrying multiple deficits in coagulation and fibrinolytic system components are highlighted.

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