New Hydroxyurea-Based Combination Therapy for Sickle Cell Disease

虽然种族和族裔人口之间的健康差距已被承认为各种系统性疾病，少数群体的健康也受到不利影响的遗传疾病，是少数群体中流行的。镰状细胞病（SCD）是一种世界性的毁灭性遗传疾病。SCD还与严重并发症如中风和高血压有关。羟基脲（HU）被引入用于治疗这种疾病，SCD患者的发病率和死亡率显著改善，这至少部分归因于HU增加了胎儿血红蛋白（Hb F）的产生。 然而，三分之一到一半的SCD患者对这种化学物质有抵抗力，并且他们的Hb F水平没有显着增加。HU的作用机制以及对HU治疗的潜在耐药性仍不清楚。该提案的长期目标是通过为SCD患者开发新的基于HU的联合疗法来改善非裔美国人的健康状况。在本提案中，我们将检验以下假设：通过结合cAMP依赖性磷酸二酯酶抑制剂，HU诱导的Hb F表达得到增强。在具体目标1中，我们将确定在HU诱导的Hb F表达中起关键作用的细胞内信号传导途径。使用CD 34+衍生的原代红系细胞，我们将研究是否HU调节已被证明参与Hb F表达的细胞内信号通路的活动。具体目标2是确定是否通过组合cAMP依赖性PDE抑制剂进一步增加HU诱导的Hb F表达。在这里，我们将利用SCD模型小鼠，其专门表达人球蛋白，包括β S球蛋白。SCD小鼠将使我们能够确认cAMP信号通路在Hb F表达中的作用，并为SCD患者开发新的基于HU的联合疗法提供实验竞技场。如果成功实施，这一建议将提高我们的理解机制，在发展过程中调节的g-珠蛋白基因的表达，并提供重要的信息，开发新的Hb F诱导剂治疗β-珠蛋白疾病，这也是常见的少数民族。

Although health disparities between racial and ethnic populations have been acknowledged for a variety of systemic diseases, minority health also has been negatively impacted by genetic disorders that are prevalent among minority groups. Sickle cell disease (SCD) is a devastating genetic disorder worldwide. SCD is also associated with serious complications such as stroke and hypertension. Hydroxyurea (HU) was introduced for the treatment of this disorder with the morbidity and mortality of SCD patients significantly improving, which is attributable at least in part to an increased production of fetal hemoglobin (Hb F) by HU. However, one third to half of SCD patients are resistant to this chemical and they demonstrate no significant increase in Hb F levels. The mechanisms of action of HU as well as those underlying resistance to HU therapy still remain unclear. The long-term goal of this proposal is to improve health conditions of African-Americans by developing novel HU-based combination therapies for SCD patients. In this proposal, we will test the hypothesis that HU-induced Hb F expression is enhanced by combining a cAMP-dependent phosphodiesterase inhibitor. In Specific Aim 1, we will determine intracellular signaling pathways that play a critical role in HU-induced Hb F expression. Using CD34+-derived primary erythroid cells, we will examine whether HU modulates the activities of intracellular signaling pathways that have been shown to be involved in Hb F expression. Specific Aim 2 is to determine whether HU-induced Hb F expression is further increased by combining a cAMP-dependent PDE inhibitor. Here we will utilize SCD model mice, which exclusively express human globins including beta S globin. SCD mice will allow us to confirm the role of cAMP signaling pathways in Hb F expression as well as to provide an experimental arena to develop novel HU-based combination therapies for SCD patients. If successfully implemented, this proposal will enhance our understanding of mechanisms that regulate the expression of the g-globin genes during development and provide important information to develop novel Hb F inducers for treating beta-globin disorders, which are also common to minority populations.