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1.
Sci Rep ; 5: 17105, 2015 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-26597678

RESUMO

The future of treating inherited and acquired genetic diseases will be defined by our ability to introduce transgenes into cells and restore normal physiology. Here we describe an autogenous transgene regulatory system (ARES), based on the bacterial lac repressor, and demonstrate its utility for controlling the expression of a transgene in bacteria, eukaryotic cells, and in the retina of mice. This ARES system is inducible by the small non-pharmacologic molecule, Isopropyl ß-D-1-thiogalactopyranoside (IPTG) that has no off-target effects in mammals. Following subretinal injection of an adeno-associated virus (AAV) vector encoding ARES, luciferase expression can be reversibly controlled in the murine retina by oral delivery of IPTG over three induction-repression cycles. The ability to induce transgene expression repeatedly via administration of an oral inducer in vivo, suggests that this type of regulatory system holds great promise for applications in human gene therapy.


Assuntos
Expressão Gênica , Terapia Genética , Ativação Transcricional/efeitos dos fármacos , Administração Oral , Animais , Dependovirus/genética , Genes Reporter , Células HEK293 , Humanos , Isopropiltiogalactosídeo/administração & dosagem , Luciferases/biossíntese , Luciferases/genética , Camundongos , Retina/metabolismo , Transgenes
2.
Sci Transl Med ; 7(291): 291ra97, 2015 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-26062849

RESUMO

Genetic pleiotropy, the phenomenon by which mutations in the same gene result in markedly different disease phenotypes, has proven difficult to explain with traditional models of disease pathogenesis. We have developed a model of pleiotropic disease that explains, through the process of basal exon skipping, how different mutations in the same gene can differentially affect protein production, with the total amount of protein produced correlating with disease severity. Mutations in the centrosomal protein of 290 kDa (CEP290) gene are associated with a spectrum of phenotypically distinct human diseases (the ciliopathies). Molecular biologic examination of CEP290 transcript and protein expression in cells from patients carrying CEP290 mutations, measured by quantitative polymerase chain reaction and Western blotting, correlated with disease severity and corroborated our model. We show that basal exon skipping may be the mechanism underlying the disease pleiotropy caused by CEP290 mutations. Applying our model to a different disease gene, CC2D2A (coiled-coil and C2 domains-containing protein 2A), we found that the same correlations held true. Our model explains the phenotypic diversity of two different inherited ciliopathies and may establish a new model for the pathogenesis of other pleiotropic human diseases.


Assuntos
Doença/genética , Éxons/genética , Pleiotropia Genética , Predisposição Genética para Doença/genética , Modelos Genéticos , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Proteínas de Ciclo Celular , Proteínas do Citoesqueleto , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Fenótipo
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