Diversity Supplement - The Role of Erythrocyte Mitochondrial Retention in Sickle Cell Disease

父级赠款摘要 镰状细胞病(SCD)是一种遗传性血液疾病，影响全球数百万人，并导致 仅在美国每年的医疗费用就至少24亿美元1-3它是由基因突变引起的 β-珠蛋白基因，导致形成血红蛋白S(HBs)。HBS在脱氧和脱氧时聚合 导致红细胞(RBC)镰状、溶血、急慢性疼痛、慢性溶血性贫血、 多系统器官损伤，以及预期寿命大大缩短。新的靶向治疗方法是 对于克服始于HBS聚合的一连串事件至关重要。最近很多 研究人员已经证明，SCD器官病理与氧化应激有关。氧化 当氧化剂增加而抗氧化剂没有类似增加时，压力就会发生。 过量的活性氧(ROS)积累会触发一连串的氧化反应，从而损害 红细胞中的脂类和蛋白质最终导致溶血或早期破坏。虽然很多 ROS介导的SCD患者并发症的研究已取得进展，进一步的研究是必要的 试图了解ROS的来源以及参与HBS聚合和溶血过程的因素。 我们已经在实验室证明了SCD红细胞保留线粒体。此外，我们已经表明， 这些保留的线粒体会产生过量的细胞内ROS，并与溶血有关。 我们的初步数据还表明，这些线粒体导致红蜘蛛体内氧气消耗增加。 血细胞。我们假设红细胞线粒体滞留导致SCD的恶化 两种非互斥机制的致病机制1)线粒体产生过量的ROS，导致 溶血和2)线粒体增加耗氧量导致细胞内低氧环境 这导致了HB S的聚合。对线粒体耗氧量及其结果的理解 SCD发病机制中的氧化应激为靶向性研究提供了新的机遇 治疗剂。红细胞线粒体源性ROS产生和耗氧量的可能性 是以前从未被研究过的新目标。我们的长期目标是将这一新发现转化为 将保留线粒体的SCD红细胞转化为治疗镰状细胞疾病的新药物疗法。

Parent Grant Abstract Sickle cell disease (SCD) is an inherited blood disorder that affects millions of people worldwide and results in healthcare costs of at least $2.4 billion per year in the United States alone.1–3 It is caused by a mutation in the β-globin gene which leads to the formation of hemoglobin S (HbS). HbS polymerizes when deoxygenated and leads to red blood cell (RBC) sickling, hemolysis, acute and chronic pain, chronic hemolytic anemia, multisystem organ damage, and a much-shortened life expectancy. Novel targeted therapeutic approaches are essential to overcome the cascade of the events that begin with HbS polymerization. Recently many investigators have demonstrated that SCD organ pathology is associated with oxidative stress. Oxidative stress occurs when there is an increase in oxidants without a similar increase in antioxidants. Excessive reactive oxygen species (ROS) accumulation triggers a cascade of oxidative reactions that damage lipids and proteins of red blood cells ultimately leading to hemolysis or early destruction. Although much progress has been made to ROS mediated complications in SCD patients, further studies are essential in an attempt to understand the source of ROS and factors involved in HbS polymerization and hemolytic process. We have demonstrated in our laboratory that SCD RBCs retain mitochondria. In addition, we have shown that these retained mitochondria create excessive intracellular ROS generation and are associated with hemolysis. Our preliminary data also show that these mitochondria cause an increased oxygen consumption in the red blood cells. We hypothesize that erythrocyte mitochondrial retention causes exacerbation of SCD pathogenesis by two non-mutually exclusive mechanisms 1) Mitochondria generate excessive ROS leading to hemolysis and 2) Mitochondria increased oxygen consumption leading to a hypoxic intracellular environment that causes Hb S polymerization. An understanding of mitochondrial oxygen consumption and consequential oxidative stress in the pathogenesis of SCD represents a novel opportunity for the development of targeted therapeutic agents. The possibility of mitochondria derived ROS generation and oxygen consumption in RBCs are novel targets that have not been investigated before. Our long-term goal is to translate the novel finding of mitochondria-retaining SCD RBCs into new pharmaceutical therapies for sickle cell disease.