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

多样性补充 - 红细胞线粒体保留在镰状细胞病中的作用

• 批准号: 10557738
• 负责人: Angela Rivers
• 金额: $ 8.6万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-08 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10557738
• 关键词: Acute Pain; Affect; Anemia; Antioxidants; Autophagocytosis; BCL2/Adenovirus E1B 19kd Interacting Protein 3-Like; Bilirubin; Blood Cells; Blood specimen; Bone Marrow; Cell Survival; Chronic; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Consequentialism; Consumption; Data; Defect; Development; Disease; Environment; Erythrocytes; Erythroid; Erythroid Progenitor Cells; Erythropoiesis; Event; Excision; Exhibits; Experimental Animal Model; FDA approved; Flow Cytometry; Functional disorder; Generations; Genes; Glutamine; Goals; Health; Health Care Costs; Hematological Disease; Hematopoietic stem cells; Hemolysis; Hemolytic Anemia; Hypoxia; Image; Individual; Inherited; Intervention; Knockout Mice; Laboratories; Life Expectancy; Link; Lipids; Longevity; Mediating; Mitochondria; Mus; Mutation; Organ; Oxidants; Oxidative Stress; Oxygen Consumption; Pain; Pathogenesis; Pathology; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Play; Polymers; Process; Proteins; Publishing; Reaction; Reactive Oxygen Species; Regulation; Research Personnel; Reticulocytes; Role; Sickle Cell; Sickle Cell Anemia; Sickle Hemoglobin; Sirolimus; Sorting - Cell Movement; Source; Spleen; Stress; Therapeutic; Translating; United States; beta Globin; chronic pain; erythroid differentiation; hydroxyurea; improved; inhibitor; mitochondrial autophagy; mitochondrial membrane; mouse model; new therapeutic target; novel; novel strategies; parent grant; peripheral blood; polymerization; precursor cell; protein function; receptor; sickling; targeted treatment; treatment strategy

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.

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，并导致 仅在美国，每年的医疗费用就至少为 24 亿美元。1-3 这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，并且 导致红细胞（RBC）镰状化、溶血、急慢性疼痛、慢性溶血性贫血、 多系统器官损伤，预期寿命大大缩短。新颖的靶向治疗方法是 对于克服从 HbS 聚合开始的级联事件至关重要。最近很多 研究人员已经证明 SCD 器官病理学与氧化应激有关。氧化性 当氧化剂增加而抗氧化剂没有类似增加时，就会产生压力。 过多的活性氧（ROS）积累会引发一系列氧化反应，从而损害 红细胞的脂质和蛋白质最终导致溶血或早期破坏。虽然很多 ROS 介导的 SCD 患者并发症已取得进展，进一步的研究至关重要 尝试了解 ROS 的来源以及参与 HbS 聚合和溶血过程的因素。 我们在实验室证明 SCD 红细胞保留线粒体。此外，我们还证明了 这些保留的线粒体会产生过多的细胞内 ROS，并与溶血有关。 我们的初步数据还表明，这些线粒体会导致红细胞耗氧量增加 血细胞。我们假设红细胞线粒体滞留导致 SCD 恶化 两种非互斥机制的发病机制 1) 线粒体产生过多的 ROS，导致 溶血和 2) 线粒体耗氧量增加导致细胞内环境缺氧 导致 Hb S 聚合。了解线粒体耗氧量及其后果 SCD 发病机制中的氧化应激为开发靶向药物提供了新的机会 治疗剂。红细胞中线粒体衍生的 ROS 生成和耗氧量的可能性 是以前从未研究过的新目标。我们的长期目标是转化这一新颖的发现 将保留线粒体的 SCD 红细胞转化为镰状细胞病的新药物疗法。