DEVELOPMENT AND ANALYSIS OF MURINE MODELS FOR SICKLE CELL ANEMIA

University Of California San Francisco, San Francisco CA

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Abstract

The long range objective of this proposal is to further our understanding of the molecular basis for sickle cell anemia with particular emphasis on examining genetic factors that contribute to the variable clinical expression of the disease. The specific goals are: (1) to characterize sickle cell disease and the factors which impact on its severity in our recently developed mouse model of sickle cell anemia, whose red cells contain exclusively human HbS; and (2) to apply genome-wide mapping tools and quantitative trait analyses to identify genetic loci unlinked to the globin cluster that modify the severity of sickle cell disease. Our first goal relates to the transgenic/gene knockout mouse model of sickle cell anemia which we generated during the previous funding period. These animals, possessing exclusively human hemoglobin HbS and no adult murine hemoglobins, are born with extensive red cell sickling and associated morbidity. We will exploit this unique model to perform detailed investigations of the pathophysiology of the disease, unavailable for study in humans. We will examine the effectiveness of agents predicted to lessen disease severity. These studies will analyze factors which have an impact on gamma-globin gene expression (i.e., hydroxyurea) and vascular tone (i.e., nitrous oxide). The second goals will employ a genome-wide scan to identify loci that alter sickle cell disease severity and globin chain switching using inbred strains of mice. These studies are divided into two parts. They will identify modified loci, using different mouse genetic backgrounds, that: (1) affect the severity of murine sickle cell disease resulting from the expression of the same human sickle transgene; and (2) affect gamma-to beta-globin switching of the same human beta-globin YAC transgene. In both of these studies, we seek to identify genes unlinked to the globin cluster in mice which are likely to impact on the severity of sickle cell disease in humans. The studies are anticipated to contribute to our improved understanding of the molecular mechanisms responsible for variable clinical expression of sickle cell disease.