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

家长补助金摘要 镰状细胞病（SCD）是一种遗传性血液疾病，影响全世界数百万人， 仅在美国，每年的医疗费用就至少为24亿美元。1 -3它是由基因突变引起的。 β-珠蛋白基因导致血红蛋白S（HbS）的形成。HbS在脱氧时聚合， 导致红细胞（RBC）镰状化、溶血、急性和慢性疼痛、慢性溶血性贫血， 多系统器官损伤预期寿命大幅缩短新的靶向治疗方法是 这对于克服以HbS聚合开始的事件级联是必要的。最近很多 研究者已经证明SCD器官病理学与氧化应激有关。氧化 当氧化剂增加而抗氧化剂没有类似增加时，就会出现压力。 过量的活性氧（ROS）积累会引发一系列氧化反应， 红细胞的脂质和蛋白质最终导致溶血或早期破坏。虽然大部分 在SCD患者中ROS介导的并发症方面已经取得了进展，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。 我们已经在实验室中证明SCD RBC保留线粒体。此外，我们还表明， 这些保留的线粒体产生过量的细胞内ROS并与溶血有关。 我们的初步数据还表明，这些线粒体导致红细胞中氧消耗增加， 血细胞我们推测红细胞线粒体滞留导致SCD加重 通过两种非相互排斥的机制发病：1）线粒体产生过量的ROS，导致 溶血和2）线粒体增加氧消耗，导致缺氧的细胞内环境 导致血红蛋白S聚合线粒体耗氧量的理解和后果 氧化应激在SCD发病机制中的作用为靶向治疗SCD提供了新的机会。 治疗剂。红细胞线粒体产生活性氧和耗氧的可能性 是以前从未研究过的新目标。我们的长期目标是将这一新发现 用于镰状细胞病的新药物疗法。

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.