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Hum Mol Genet ; 22(3): 493-507, 2013 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-23100326

RESUMO

Ataxia telangiectasia (A-T) is a highly pleiotropic disorder. Patients suffer from progressive neurodegeneration, severe bronchial complications, immunodeficiency, hypersensitivity to radiotherapy and elevated risk of malignancies. Leukemia and lymphoma, along with lung failure, are the main causes of morbidity and mortality in A-T patients. At present, no effective therapy for A-T exists. One promising therapeutic approach is bone marrow transplantation (BMT) that is already used as a curative therapy for other genomic instability syndromes. We used an established clinically relevant non-myeloablative host-conditioning regimen and transplanted green fluorescent protein (GFP)-expressing ataxia telangiectasia mutated (ATM)-competent bone marrow-derived cells (BMDCs) into Atm-deficient mice. GFP expression allowed tracking of the potential migration of the cells into the tissues of recipient animals. Donor BMDCs migrated into the bone marrow, blood, thymus, spleen and lung tissue of Atm-deficient mice showing an ATM-competent phenotype. BMT inhibited thymic lymphomas, normalized T-lymphocyte populations, improved weight gain and rearing activity of Atm-deficient mice. In contrast, no GFP(+) cells were found in the cerebellum or cerebrum, and we detected decreased size index in MRI imaging of the cerebellum in 8-month-old transplanted Atm-deficient mice in comparison to wild-type mice. The repopulation with ATM-competent BMDCs is associated with a prolonged lifespan and significantly improved the phenotype of Atm-deficient mice.


Assuntos
Ataxia Telangiectasia/terapia , Transplante de Medula Óssea , Proteínas de Ciclo Celular/genética , Movimento Celular , Proteínas de Ligação a DNA/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Supressoras de Tumor/genética , Animais , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/patologia , Proteínas Mutadas de Ataxia Telangiectasia , Barreira Hematoencefálica/metabolismo , Western Blotting , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Proteínas de Ciclo Celular/metabolismo , Quimerismo , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Genótipo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Pulmão/citologia , Pulmão/metabolismo , Imageamento por Ressonância Magnética , Camundongos , Camundongos Transgênicos , Transplante de Células-Tronco de Sangue Periférico , Fenótipo , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Baço/metabolismo , Timo/metabolismo , Proteínas Supressoras de Tumor/metabolismo
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