Developmental regulation of human beta-like globin gene switching is controlled by several parameters, primarily the trans-acting transcriptional milieu and cis-acting DNA elements. Molecular control of globin gene switching provides a paradigm for understanding the dynamics of mammalian gene expression during ontogeny. Unraveling the mechanisms underlying beta-like globin gene switching, particularly those involved in fetal hemoglobin F (Hb F) induction, will have enormous benefit to patients suffering from a variety of hemoglobinopathies, since the general consensus within the scientific community is that sustained expression of the gamma-globin genes in adults will be palliative to these diseases. Transactivation of fetal gamma-globin gene expression has important therapeutic application for the treatment of sickle cell anemia and Cooley's anemia, as well as certain beta-thalassemias.
The Specific Aims of this research are to (1) validate the fetal specificity of already identified trans-acting proteins that activate fetal globin synthesis using novel erythroid cell lines derived from human beta-globin locus yeast artificial chromosome (beta-YAC) transgenic mice, (2) verify the fetal specificity of the same transactivators during development in an animal model by over-expression of these proteins in beta-YAC transgenic mice, (3) develop an assay system to identify new, or test existing, pharmacologic compounds that induct fetal gamma-globin gene expression without activating adult beta-globin gene expression using simultaneous measurement of both globin gene products, and (4) clone new transcriptional activators of gamma- globin gene expression from human fetal liver or GM 979 cell cDNA libraries.
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