Project: Research project

Project Details


DESCRIPTION (adapted from the application)

Sickle cell anemia and related hemoglobinopathies are among the most common
genetic disorders in this country. Reactivation of fetal globin by
pharmacologic agents provides therapeutic benefits in these patients by
interfering with the polymerization of the mutant hemoglobin. This proposal
outlines an alternative approach for augmentation of fetal hemoglobin.

All vertebrate animals switch hemoglobins during development from fetal to
adult type. The molecular mechanisms that mediate this process are complex.
Erythroid Kruppel like factor (EKLF) is an erythroid specific transcription
factor that plays a crucial role in activating beta globin expression and in
consolidating the switch from fetal to adult globin. In its absence not only is
adult beta globin expression abolished, but there is a competitive increase in
gamma globin expression. This has led us to consider whether manipulating
EKLF's molecular properties so that it acts as a transcriptional repressor
might further augment and stabilize gamma globin gene expression.

The above hypothesis will be tested by: (1) Constructing repressor EKLF
constructs and testing them by transient transfection assays in cell lines. (2)
Monitoring the functional importance of repressor constructs in differentiating
embryonic stem cells and transgenic mice.(3) Analyzing the effect of repressor
constructs on sickle erythropoiesis in liquid cultures.

The end result of these aims will be to provide a transcriptional reagent for
gene therapy approaches that will augment fetal hemoglobin levels in patients
with sickle cell disease. Amelioration of the debilitating effects of this
disease provides a considerable clinical rationale for pursuing this goal.
Effective start/end date9/30/008/31/05


  • Cell Biology
  • Genetics


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