STUDIES OF NF-E4, A NOVEL FETAL/ERYTHROID SPECIFIC FACTOR INVOLVED IN FETAL GLOBIN GENE REGULATION

镰状细胞性贫血和地中海贫血是世界上最常见的遗传性疾病。受影响的人遭受毁灭性的临床后遗症，生命头20年的死亡率仍然很高。这些疾病的治疗依赖于用功能正常的血红蛋白替代受影响或缺失的血红蛋白蛋白质链。这在罕见的患者中是明显的，他们共同遗传了一种提高胎儿血红蛋白（HbF）的天然突变，因为这些患者的临床病程得到了显着改善。因此，应探索出生后重新激活胎儿珠蛋白基因表达的治疗策略。为了实现这一目标，我们必须进一步了解珠蛋白基因表达的发育调控的正常机制。为此，我们最近发现了一个新的基因，这是胎儿珠蛋白表达的关键。我们在这里提出的研究将进一步确定该基因的功能，并评估其对镰状细胞病和地中海贫血的基因治疗潜力。

Sickle cell anemia and thalassemia are the commonest genetic disorders worldwide. Those affected suffer devastating clinical sequelae and mortality in the first twenty years of life remains high. A cure for these diseases is dependent on the replacement of the affected or absent hemoglobin protein chains with normally functioning hemoglobins. This is evident in rare patients who co-inherit a natural mutation which elevates fetal hemoglobin (HbF), as these patients have a dramatically ameliorated clinical course. Therefore, treatment strategies which could reactivate fetal globin gene expression after birth should be explored for these diseases. To achieve this goal we must further our understanding of the normal mechanisms of developmental regulation of globin gene expression. To this end we have recently identified a novel gene which is critical for fetal globin expression. The studies we propose here will further define the function of this gene and assess its potential for gene therapy for sickle cell disease and thalassemia.