Abnormalities of the beta-globin gene cause significant morbidity and mortality throughout the world. The goal of the proposed research is to express the human beta-globin gene in hematopoietic progenitor cells, in order to explore the use of somatic gene therapy for the treatment of these diseases. The general strategy for the researcher involves: (1) construction of retroviral vectors containing the human beta-globin gene and its dominant control region; (2) transfer of these vectors into murine and human hematopoietic progenitor cells; (3) injecting the transduced cells into lethally irradiated mice and assaying the transduced cells and their progeny cultured either in vitro or in vivo for proviral DNA, beta-globin RNA, and beta-globin protein. This research project will cover the following issues. Does the recently described dominant control region of the human beta-globin gene increase beta-globin expression when the gene and the control region are transferred by retrovirus into hematopoietic progenitor cells? Is the beta-globin gene that has been transferred into beta-thalassemic mice expressed at levels high enough to affect the phenotype of beta-thalassemic mice? Exploring these issues will further develop the framework for gene transfer to treat genetic diseases. The over-all aim of this physician-scientist award is to educate and train the candidate to become an independent investigator in molecular biology research, and to prepare the candidate for a career in academic medicine in the field of hematology.
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| Lowenstein, C J; Glatt, C S; Bredt, D S et al. (1992) Cloned and expressed macrophage nitric oxide synthase contrasts with the brain enzyme. Proc Natl Acad Sci U S A 89:6711-5 |
