Hematology has been at the forefront of the application of molecular genetics to the analysis and treatment of genetic diseases. Although the molecular bases of many inherited (e.g. sickle cell anemia, thalassemia) and acquired (e.g. leukemias) hematologic disorders are well defined, we do not have a full understanding of the mechanisms by which hematopoietic cells develop. An appreciation of this fundamental problem will likely provide important insights into diverse issues pertinent to blood cell development, including mechanisms by which cell fates are determined during embryogenesis, by which a choice between self-renewal (proliferation) and differentiation is made by hematopoietic stem cells, by which specific lineages are chosen during progenitor development, and by which aberrant gene expression consequent to chromosomal translocations provide leads to leukemia. Increased understanding of these areas is also likely to provide important new directions in on-going efforts to express foreign sequences following gene transfer into hematopoietic cells for either experimental or therapeutic purposes. The proposed Center of Excellence in Molecular Hematology at the children's Hospital, Harvard Medical School, is organized to attack fundamental molecular hematopoiesis. The Center includes four principal research projects (PIs: Drs. Orkin, Greenberg, Zon, and Mathey-Prevot), two core units (an ES tissue culture mouse core and a zebrafish core facility), and a pilot project program. The principal projects address the role of specific genes in hematopoietic development (E2F1, E2F2, SCL) through knock-outs in mice, the function of the hematopoietic growth factor IL-3 in a test cell line and the specificity of chimeric erythropoietin receptors through gene targeting, and the basis of blood cell deficiency in zebrafish mutants. These studies will be complemented by pilot projects dealing with the role of a new gene (tel) in leukemogenesis, protein-protein interactions of SH3 and PH domains of spectrin, and nuclear assembly in yeast. A major goal of the Center in the longterm is interaction with and involvement of other research groups in the Harvard Medical area, largely through collaborative experiments with the two core units. In this manner the Center will serve to move research in the field ahead and recruit new investigators into molecular hematology.
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