Sickle Cell Disease, Globin Gene Regulation.
Fetal hemoglobin inhibits the primary pathophysiology of sickle cell disease through the formation of an asymmetric hemoglobin hybrid with sickle hemoglobin. Work in this area has successfully identified the hybrid hemoglobin (FS; a2gbS) in patients' samples by a novel application of mass spectrometry, and confirms the underlying mechanism for the mild phenotype of sickle cell disease in individuals with persistent fetal globin expression. These findings underlie the rationale for research aimed at identifying agents for reactivating the fetal globin gene in sickle cell disease.
Studies on the effect of naturally occurring DNA sequence variation suggest that polymorphisms that limit the expression of sickle globin play an important role in determining the amount of fetal globin in patients with sickle cell disease. We are currently developing an antisense strategy to limit the synthesis of sickle globin. Concurrent inhibition of sickle hemoglobin and augmented fetal hemoglobin expression offers a potentially powerful strategy to reduce the clinical severity of sickle cell disease.
Work in our laboratory is actively unraveling the roles of the signal transducers and activators of transcription (STAT) and p38 mitogen activating protein kinase signaling pathways in g globin regulation. There is evidence from this work that a variant of STAT3 acting in concert with other transcription factors is involved in silencing the g globin gene. Our focus is to identify factors in this pathway that regulate the fate of fetal hemoglobin producing cells
Sickle Cell Disease, Globin Gene Regulation.
