Expression of the Wilson disease gene is deficient in the Long-Evans Cinnamon rat.
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ABSTRACT:
SUBMITTER: Yamaguchi Y
PROVIDER: S-EPMC1137132 | biostudies-other | 1994 Jul
REPOSITORIES: biostudies-other
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Project description:Long Evans rat strains are applied as research models in a broad spectrum of biomedical fields (>15,800 citations, NCBI PubMed). Here, we report an approach to genetically modify the Long Evans rat germline in donor spermatogonial stem cells. Long Evans rat spermatogonial lines were derived from freshly isolated laminin-binding spermatogonia. Laminin-binding spermatogonia were cultured over multiple passages on fibroblast feeder layers in serum-free culture medium containing GDNF and FGF2. Long Evans rat spermatogonial lines were genetically modified by transposon transduction to express a germline, tdTomato reporter gene. Donor rat spermatogonial lines robustly regenerated spermatogenesis after transplantation into testes of busulfan-treated, allogenic, Long Evans rats. Donor-derived spermatogenesis largely restored testis size in the chemically sterilized, recipient Long Evans rats. Recipient Long Evans rats stably transmitted the tdTomato germline marker to subsequent generations. Overall, Long Evans rat spermatogonial lines provided effective donor germline vectors for genetically modifying Long Evans rats.
| S-EPMC7336504 | biostudies-literature
Project description:Streptococcus agalactiae breed:Long-Evans Rat Genome sequencing and assembly
| PRJNA342556 | ENA
Project description:AimTo investigate the impact of dietary copper given at different time points on the onset of fulminant hepatitis.MethodsThe Long-Evans cinnamon (LEC) rat model of Wilson's disease (WD) was used to study the impact of high dietary copper (hCu) on the induction of fulminant hepatitis at early or late time points of life. High Cu diet was started in rat pups or in adults (month 5) for three months. Animals that received reduced dietary copper (rCu) throughout their lifetime served as a control. Hepatitis-associated serum markers (alanine aminotransferase, aspartate transaminase, bilirubin) were analyzed in animal groups receiving hCu or rCu. Liver copper content and liver histology were revealed at sacrifice. A set of 5 marker genes previously found to be affected in injured liver and which are related to angiogenesis (Vegfa), fat metabolism (Srebf1), extracellular matrix (Timp1), oxidative stress (Hmox1), and the cell cycle (Cdkn1a) were analyzed by real-time polymerase chain reaction.ResultsRegardless of the time point when hCu was started, LEC rats (35/36) developed fulminant hepatitis and died. Animals receiving rCu (36/36) remained healthy, did not develop hepatitis, and survived long term without symptoms of overt disease, although liver copper accumulated in adult animals (477 ± 75 μg/g). With regard to start of hCu, onset of fulminant hepatitis was significantly (P < 0.001) earlier in adults (35 ± 9 d) that showed pre-accumulation of liver copper as compared to the pup group (77 ± 15 d). Hepatitis-associated serum markers, liver copper and liver histology, as well as gene expression, were affected in LEC rats receiving hCu. However, except for early and rapid onset of hepatitis, biochemical and molecular markers were similar at the early and late time points of disease.ConclusionRapid onset of fulminant hepatitis in asymptomatic LEC rats with elevated liver copper suggests that there is a critical threshold of liver copper which is important to trigger the course of WD.
| S-EPMC3482640 | biostudies-literature
Project description:BackgroundWilson's disease (WD) is an inherited disorder of copper metabolism leading to liver failure and/or neurological impairment. Its diagnosis often remains difficult even with genetic testing. Relative exchangeable copper (REC) has recently been described as a reliable serum diagnostic marker for WD.Methodology/principal findingsThe aim of this study was to validate the use of REC in the Long Evans Cinnamon (LEC) rat, an animal model for WD, and to study its relevance under different conditions in comparison with conventional markers. Two groups of LEC rats and one group of Long-Evans (LE) rats were clinically and biologically monitored from 6 to 28 weeks of age. One group of LEC rats was given copper-free food. The other groups had normal food. Blood samples were collected each month and different serum markers for WD (namely ceruloplasmin oxidase activity, exchangeable copper (CuEXC), total serum copper and REC) and acute liver failure (serum transaminases and bilirubinemia) were tested. Every LEC rat under normal food developed acute liver failure (ALF), with 40% global mortality. Serum transaminases and bilirubinemia along with total serum copper and exchangeable copper levels increased with the onset of acute liver failure. A correlation was observed between CuEXC values and the severity of ALF. Cut-off values were different between young and adult rats and evolved because of age and/or liver failure. Only REC, with values >19%, was able to discriminate LEC groups from the LE control group at every time point in the study. REC sensitivity and specificity reached 100% in adults rats.Conclusions/significanceREC appears to be independent of demographic or clinical data in LEC rats. It is a very simple and reliable blood test for the diagnosis of copper toxicosis owing to a lack of ATP7B function. CuEXC can be used as an accurate biomarker of copper overload.
| S-EPMC3866119 | biostudies-literature
Project description:In Wilson disease (WD), functional loss of ATPase copper-transporting ? (ATP7B) impairs biliary copper excretion, leading to excessive copper accumulation in the liver and fulminant hepatitis. Current US Food and Drug Administration- and European Medicines Agency-approved pharmacological treatments usually fail to restore copper homeostasis in patients with WD who have progressed to acute liver failure, leaving liver transplantation as the only viable treatment option. Here, we investigated the therapeutic utility of methanobactin (MB), a peptide produced by Methylosinus trichosporium OB3b, which has an exceptionally high affinity for copper. We demonstrated that ATP7B-deficient rats recapitulate WD-associated phenotypes, including hepatic copper accumulation, liver damage, and mitochondrial impairment. Short-term treatment of these rats with MB efficiently reversed mitochondrial impairment and liver damage in the acute stages of liver copper accumulation compared with that seen in untreated ATP7B-deficient rats. This beneficial effect was associated with depletion of copper from hepatocyte mitochondria. Moreover, MB treatment prevented hepatocyte death, subsequent liver failure, and death in the rodent model. These results suggest that MB has potential as a therapeutic agent for the treatment of acute WD.
| S-EPMC4922707 | biostudies-literature
Project description:To determine whether immortalized cells derived from the rat SCN (SCN 2.2) retain intrinsic rhythm-generating properties characteristic of the SCN, oscillatory properties of the SCN2.2 transcriptome were analyzed and compared to those found in the rat SCN in vivo using rat U34A Affymetrix GeneChips. In this comparison, adult male Long-Evans rats (175-200g; N=45) were housed under a standard 12h light:12h dark photoperiod (LD 12:12; lights-on at 0600 hr). At 1800 hr (circadian time [CT] 12), animals were exposed to constant darkness (DD) and 12 hours later (0600 hr or CT 0), sacrificed under isoflurane anesthesia at 6-hr intervals (N=5) for 48 hours by decapitation using an infrared viewer. After the eyes were removed in the dark, SCN tissue was immediately dissected under dim light, frozen in liquid nitrogen, and stored at â??800C. SCN tissue from individual animals was separately homogenized in TRIzol reagent by aspiration through a 25-gauge needle and then extracted cellular RNA for all animals at each timepoint was pooled into a single sample. RNA samples were subjected to on-column treatment with DNAse-1 to digest genomic DNA and then were stored at â??80°C before routine processing for GeneChip analysis.
2008-06-11 | E-GEOD-1673 | biostudies-arrayexpress
Project description:Rats are highly social creatures that produce ultrasonic vocalizations (USVs) during social interactions. Brattleboro rats, a Long-Evans derived rat that lacks vasopressin (AVP) due to a mutation in the Avp gene, exhibit atypical social behavior, including fewer USVs with altered spectrotemporal characteristics during social interactions. It is unclear why Brattleboro rats produce atypical USVs, but one factor could be differences in auditory acuity between them and wild-type Long Evans rats with functional vasopressin. Previous studies have suggested a link between increased levels of AVP and auditory processing. Additionally, few studies have investigated sex differences in auditory perception by Long-Evans rats. Sex differences in auditory acuity have been found throughout the animal kingdom, but have not yet been demonstrated in rat audiograms. This study aimed to measure auditory brainstem response (ABR) derived audiograms for frequencies ranging from 1 to 64 kHz in male and female homozygous Brattleboro (Hom), heterozygous Brattleboro (Het), and wild-type (WT) Long-Evans rats to better understand the role of AVP and sex differences in auditory processing by these rats. We failed to detect significant differences between the ABR audiograms of Hom, Het, and WT Long-Evans rats, suggesting that varying levels of AVP do not affect auditory processing. Interestingly, males and females of all genotypes did differ in their ABR thresholds, with males exhibiting higher thresholds than females. The sex differences in auditory acuity were significant at the lowest and highest frequencies, possibly affecting the perception of USVs. These are the first known sex differences in rat audiograms.
| S-EPMC6716658 | biostudies-literature
Project description:Background:Chronic feeding plus binge administration of ethanol causes very high blood alcohol concentrations. However, its co-administration with tobacco Nicotine-Derived Nitrosamine Ketone (NNK) results in somewhat lower blood alcohol levels, suggesting that NNK and therefore smoking, alters alcohol metabolism in the liver. To explore this hypothesis, we examined effects of ethanol and/or NNK exposures on the expression and activity levels of enzymes that regulate their metabolism in liver. Methods:This study utilized a 4-way model in which Long Evans rats were fed liquid diets containing 0% or 26% ethanol for 8 weeks, and respectively i.p injected with saline or 2 g/kg of ethanol 3 times/week during Weeks 7 and 8. The control and ethanol-exposed groups were each sub-divided and further i.p treated with 2 mg/kg of NNK or saline (3×/week) in Weeks 3-8. ADH, catalase and ALDH activities were measured using commercial kits. CYP450 mRNA levels (17 isoforms) were measured by qRT-PCR analysis. Results:Ethanol significantly increased hepatic ADH but not catalase or ALDH activity. NNK had no effect on ADH, ALDH, or catalase, but when combined with ethanol, it increased ADH activity above the levels measured in all other groups. Ethanol increased CYP2C7, while NNK increased CYP2B1 and CYP4A1mRNA levels relative to control. In contrast, dual ethanol + NNK exposures inhibited CYP2B1 and CYP4A1 expression relative to NNK. Conclusion: Dual exposures to ethanol and NNK increase hepatic ethanol metabolism, and ethanol and/or NNK exposures alter the expression of CYP450 isoforms that are utilized in NNK and fatty acid metabolism.
| S-EPMC5898820 | biostudies-literature
Project description:Wilson disease (WD) is a rare hereditary condition that is caused by a genetic defect in the copper-transporting ATPase ATP7B that results in hepatic copper accumulation and lethal liver failure. The present study focuses on the structural mitochondrial alterations that precede clinical symptoms in the livers of rats lacking Atp7b, an animal model for WD. Liver mitochondria from these Atp7b–/– rats contained enlarged cristae and widened intermembrane spaces, which coincided with a massive mitochondrial accumulation of copper. These changes, however, preceded detectable deficits in oxidative phosphorylation and biochemical signs of oxidative damage, suggesting that the ultrastructural modifications were not the result of oxidative stress imposed by copper- dependent Fenton chemistry. In a cell-free system containing a reducing dithiol agent, isolated mitochondria exposed to copper underwent modifications that were closely related to those observed in vivo. In this cell-free system, copper induced thiol modifications of three abundant mitochondrial membrane proteins, and this correlated with reversible intramitochondrial membrane crosslinking, which was also observed in liver mitochondria from Atp7b–/– rats. In vivo, copper-chelating agents reversed mitochondrial accumulation of copper, as well as signs of intra-mitochondrial membrane crosslinking, thereby preserving the functional and structural integrity of mitochondria. Together, these findings suggest that the mitochondrion constitutes a pivotal target of copper in WD.
| S-EPMC3068979 | biostudies-literature
Project description:To determine whether immortalized cells derived from the rat SCN (SCN 2.2) retain intrinsic rhythm-generating properties characteristic of the SCN, oscillatory properties of the SCN2.2 transcriptome were analyzed and compared to those found in the rat SCN in vivo using rat U34A Affymetrix GeneChips. In this comparison, adult male Long-Evans rats (175-200g; N=45) were housed under a standard 12h light:12h dark photoperiod (LD 12:12; lights-on at 0600 hr). At 1800 hr (circadian time [CT] 12), animals were exposed to constant darkness (DD) and 12 hours later (0600 hr or CT 0), sacrificed under isoflurane anesthesia at 6-hr intervals (N=5) for 48 hours by decapitation using an infrared viewer. After the eyes were removed in the dark, SCN tissue was immediately dissected under dim light, frozen in liquid nitrogen, and stored at –800C. SCN tissue from individual animals was separately homogenized in TRIzol reagent by aspiration through a 25-gauge needle and then extracted cellular RNA for all animals at each timepoint was pooled into a single sample. RNA samples were subjected to on-column treatment with DNAse-1 to digest genomic DNA and then were stored at –80°C before routine processing for GeneChip analysis. Keywords: other
2004-10-09 | GSE1673 | GEO