<i>Atp7b</i>
          −/− mice as a model for studies of Wilson's disease

Lutsenko, Svetlana

doi:10.1042/bst0361233

Cited by 91 publications

(68 citation statements)

References 42 publications

(64 reference statements)

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“…Despite massive accumulation of copper in a cytosol, copper incorporation into ceruloplasmin is impaired and serum levels and activity of ceruloplasmin are greatly diminished (phenotypically resembling consequences of copper deficiency, Figure 2). The genetically engineered knockouts of Atp7b (Atp7b-/-mice) accurately reproduce these key features of WD (77). Consequently, these animals have been used to investigate consequences of copper overload at the molecular level.…”

Section: Copper Overload In Wilson's Disease Markedly Alters Lipid Mementioning

confidence: 99%

The Role of Copper as a Modifier of Lipid Metabolism

Burkhead¹,

Lutsenko²

2013

Lipid Metabolism

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Section: Copper Overload In Wilson's Disease Markedly Alters Lipid Mementioning

confidence: 99%

The Role of Copper as a Modifier of Lipid Metabolism

Burkhead¹,

Lutsenko²

2013

Lipid Metabolism

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“…−∕− mouse model is particularly attractive owing to its phenotypic and metabolic similarities to Wilson disease in humans and its preparation by targeted inactivation of a single gene, which ensures that any disease phenotypes reflect only the consequences of the loss of ATP7B function (14,(56)(57)(58). Specifically, a series of 7-to 11-wk-old WT and Atp7b −∕− female mice were injected with CS790AM and imaged at 5, 30, and 60 min after injection.…”

Section: Cs790am Visualizes Dynamic Changes Inmentioning

confidence: 99%

Near-infrared fluorescent sensor for in vivo copper imaging in a murine Wilson disease model

Hirayama¹,

Bittner²,

Gray

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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197

138

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Copper is an essential metal nutrient that is tightly regulated in the body because loss of its homeostasis is connected to severe diseases such as Menkes and Wilson diseases, Alzheimer’s disease, prion disorders, and amyotrophic lateral sclerosis. The complex relationships between copper status and various stages of health and disease remain challenging to elucidate, in part due to a lack of methods for monitoring dynamic changes in copper pools in whole living organisms. Here we present the synthesis, spectroscopy, and in vivo imaging applications of Coppersensor 790, a first-generation fluorescent sensor for visualizing labile copper pools in living animals. Coppersensor 790 combines a near-infrared emitting cyanine dye with a sulfur-rich receptor to provide a selective and sensitive turn-on response to copper. This probe is capable of monitoring fluctuations in exchangeable copper stores in living cells and mice under basal conditions, as well as in situations of copper overload or deficiency. Moreover, we demonstrate the utility of this unique chemical tool to detect aberrant increases in labile copper levels in a murine model of Wilson disease, a genetic disorder that is characterized by accumulation of excess copper. The ability to monitor real-time copper fluxes in living animals offers potentially rich opportunities to examine copper physiology in health and disease.

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“…Copper levels may not be the best measure of morbidity given that the detrimental effects of copper on the hepatocyte are still not fully understood. 20 Our data suggest that a partial, but incomplete correction of liver copper content was sufficient to alleviate many parameters of liver injury in all mice. The absence of gross and histological pathology, the restoration of holoceruloplasmin and lipid biosynthesis and the lack of liver transaminase elevation were all a result of human ATP7B expression in the knockout mice.…”

Section: Discussionmentioning

confidence: 64%

Early gestational gene transfer with targeted ATP7B expression in the liver improves phenotype in a murine model of Wilson's disease

et al. 2011

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The ideal gene therapy for metabolical liver disorders would target hepatocytes before the onset of disease and be durable, non-toxic and non-immunogenic. Early gestational gene transfer can achieve such goals. Here, we demonstrate that prenatal gene transfer of human Atp7b reduces liver pathology and improves biochemical markers in Atp7b À/À mice, a murine model of Wilson's disease (WD). Following prenatal injection of lentivirus vector containing the human Atp7b gene under the transcriptional control of a liver-specific promoter, the full-length ATP7B was detectable in mouse livers for the entire duration of experiments (20 weeks after birth). In contrast to a marked pathology in non-injected animals, livers from age-matched treated mice consistently demonstrated normal gross and histological morphology. Hepatic copper content was decreased in the majority of treated mice, although remaining copper levels varied. Improvement of hepatic copper metabolism was further apparent from the presence of copper-bound ceruloplasmin in the sera and normalization of the mRNA levels for HMG CoAreductase. With this approach, the complete loss of copper transport function can be ameliorated, as evident from phenotypical improvement in treated Atp7b À/À mice. This study provides proof of principle for in utero gene therapy in WD and other liver-based enzyme deficiencies.

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Atp7b −/− mice as a model for studies of Wilson's disease

Cited by 91 publications

References 42 publications

The Role of Copper as a Modifier of Lipid Metabolism

The Role of Copper as a Modifier of Lipid Metabolism

Near-infrared fluorescent sensor for in vivo copper imaging in a murine Wilson disease model

Early gestational gene transfer with targeted ATP7B expression in the liver improves phenotype in a murine model of Wilson's disease

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