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http://documenta.ciemat.es/handle/123456789/2355
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Título : | Hematopoietic dysfunction in a mouse model for Fanconi anemia group D1 |
Autor : | Navarro, S Meza, MW Quintana-Bustamante, O Casado, JA Jacome, A McAllister, K Puerto, S Surrallés, J Segovia, JC Bueren, JA |
Fecha de publicación : | jul-2006 |
Editorial : | Molecular Therapy |
Resumen : | We have investigated the hematopoietic phenotype of mice with a hypomorphic mutation in the Brca2/Fancd1 gene (Brca2(Delta27/Delta27) mutation). In contrast to observations made in other Fanconi anemia (FA) mouse models, low numbers of hematopoietic colony-forming cells (CFCs) were noted in Brca2(Delta27/Delta27) mice, either young or adult. Additionally, a high incidence of spontaneous chromosomal instability was observed in Brca2(Delta27/Delta27) bone marrow (BM) cells, but not in Brca2(+/Delta27) or Fanca(-/-) BM cells. Although Brca2(Delta27/Delta27) CFCs were not hypersensitive to ionizing radiation, a very severe hematopoietic syndrome was observed in irradiated Brca2(Delta27/Delta27) mice. Conventional BM competition experiments showed a marked repopulation defect in Brca2(Delta27/Delta27) hematopoietic stem cells (HSCs), compared to wild-type HSCs. Moreover, we have observed for the first time in a DNA repair disease model a very significant proliferation defect in Brca2(Delta27/Delta27) HSCs maintained in their natural physiological environment. The progressive repopulation of wild-type HSCs transplanted into unconditioned Brca2(Delta27/Delta27) recipients is reminiscent of the somatic mosaicism phenomenon observed in a number of genetic diseases, including FA. The hematopoietic phenotype associated with the Brca2(Delta27/Delta27) mutation suggests that this FA-D1 mouse model will constitute an important tool for the development of new therapies for FA, including gene therapy. |
URI : | http://documenta.ciemat.es/handle/123456789/2355 |
Aparece en las colecciones: | Tesis y trabajos académicos de Investigación Básica
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