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确认为各种系统性疾病，但少数群体的健康也受到少数群体中普遍存在的遗传疾病的负面影响。镰状细胞病(SCD)是一种世界性的遗传性疾病。SCD还与中风和高血压等严重并发症有关。羟基脲(HU)被用于治疗这种疾病，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具有抵抗力，他们的Hb F水平没有显著增加。HU的作用机制以及对HU治疗的潜在耐药性仍不清楚。这项提案的长期目标是通过为SCD患者开发基于HU的新型联合疗法来改善非裔美国人的健康状况。在这项提案中，我们将检验HU诱导的Hb F表达通过结合cAMP依赖的磷酸二酯酶抑制剂而增强的假设。在特定的目标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通路。利用CD34来源的原代红系细胞，我们将研究HU是否调节细胞内信号通路的活性，这些信号通路已被证明参与Hb F的表达。特异目的2是确定HU诱导的HbF表达是否通过结合cAMP依赖的PDE抑制剂而进一步增加。在这里，我们将利用SCD模型小鼠，它只表达人珠蛋白，包括β-S珠蛋白。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，并为开发SCD患者基于HU的新型联合疗法提供实验平台。如果成功实施，这一建议将加强我们对g-珠蛋白基因在发育过程中表达调控机制的理解，并为开发新的Hb-F诱导剂治疗β-珠蛋白紊乱提供重要信息，这种疾病在少数族裔人群中也很常见。

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.