Mitophagy as Potential Target in Sickle Cell Disease

线粒体自噬作为镰状细胞病的潜在靶标

• 批准号: 9228639
• 负责人: Angela Rivers
• 金额: $ 8万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9228639
• 关键词: Accounting; Acute Pain; Adult; Affect; Anemia; Autophagocytosis; Basophilic Erythroblast; Birth; Blood; Blood Circulation; Bone Marrow; Carbon Dioxide; Caring; Cells; Cellular Metabolic Process; Chronic; Cytolysis; Data; Defect; Development; Disease; Endoplasmic Reticulum; Epigenetic Process; Erythroblasts; Erythrocytes; Erythropoiesis; Exocytosis; FDA approved; FRAP1 gene; Fetal Hemoglobin; Gene Expression; Genes; Globin; Glutamic Acid; Goals; Golgi Apparatus; Grant; Health Care Costs; Hematological Disease; Hemoglobin; Hemoglobin concentration result; Individual; Inherited; Knock-out; Label; Lead; Life Expectancy; Link; Longevity; Lysine; Maintenance; Marrow; Metabolism; Mitochondria; Modification; Molecular; Mus; Mutation; Organ; Organelles; Oxygen; Pain; Papio; Pathology; Pathway interactions; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Polychromatophilic Erythroblast; Pronormoblasts; Reactive Oxygen Species; Reporting; Respiration; Reticulocytes; Scheme; Shapes; Sickle Cell; Sickle Cell Anemia; Sickle Hemoglobin; Symptoms; United States; Vacuole; Valine; base; chronic pain; cost; data reduction; effective therapy; gamma Globin; hydroxyurea; inhibitor/antagonist; mouse model; novel; polymerization; progenitor; restoration; sickling; treatment strategy

Sickle cell disease (SCD) is an inherited blood disorder that affects millions of people worldwide. In the United States, approximately 100,000 people have it, with heath care costs estimated to be $1.1 billion in the US alone. It is caused by a mutation in the γ-globin gene, causing glutamic acid to be substituted by valine. Because of this, when deoxygenated, the hemoglobin is able to polymerize, causing shape change of the red blood cell (RBC), RBC lysis, and innumerable other complications including acute and chronic pain, chronic anemia, multisystem organ damage, and a much shortened life expectancy. The symptoms appear shortly after birth, when fetal hemoglobin (HbF) levels decline, and are replaced by adult sickle hemoglobin. Because of this observation, much effort has been placed to induce fetal hemoglobin levels in those with SCD. Hydroxyurea, the only FDA approved drug for the treatment of SCD, is unfortunately effective in only about 50% of those who take it, and its mechanism is not clear. Therefore, our lab investigates alternate treatments for SCD in the SCD mouse model. It is believed that the red blood cell (RBC) is the most common cell in the body. In order to maintain a normal amount of hemoglobin to carry oxygen and remove carbon dioxide, adult humans, make more than 2 million red blood cells a second! This is the result of a highly orchestrated plan. Erythropoiesis in adult humans originates in the bone marrow and follows a path from progenitor to precursor to mature red blood cells. They follow the developmental scheme of the proerythroblast, followed by the basophilic erythroblast, the polychromatophilic erythroblast, and then the orthochromatic erythroblast. These are followed by reticulocytes, which are enucleated, and lose their organelles, and migrate from the marrow to the peripheral circulation. They normally account for 0.5 to 1.5% of all red blood cells, in those who are anemic, the percent increases. Reticulocytes have been found to have large vacuolar inclusions, which label for markers of the endoplasmic reticulum, Golgi, and mitochondria. It is thought that these vacuoles are eliminated by exocytosis and autophagy. PGCα1 is known to induce regulators of mitophagy and mitochondrial respiration. Recent studies on a knockout (Nix -/-) mouse also demonstrated the lack of mitophagy led to the short life span of RBCs Our preliminary data from untreated sickle cell mice show mature red blood cells retain mitochondria at a higher level than controls. The higher number of mitochondria rich reticulocytes in circulating blood could potentially promote the elevated levels of reactive oxygen species, changes in oxygen metabolism and the cell lysis seen in the disease. The molecular mechanism of increased mitochondria in red blood cells associated with SCD is not clear. Mitophagy regulated through the mammalian Target of Rapamycin (m-TOR) dependent and independent mitophagy pathway. This proposal seeks to provide pilot data that will link aberrant mitophagy with sickle cell pathology and develop new strategies for the treatment of SCD using mitophagy restoration drugs. Our goal is to obtain preliminary data that the reductions of mitochondrial retention in RBC will provide safe and effective therapy in SCD mouse.

镰状细胞病（SCD）是一种遗传性血液疾病，影响全球数百万人。在联合 在美国，大约有10万人患有这种疾病，美国的医疗费用估计为11亿美元 一个人它是由γ-珠蛋白基因突变引起的，导致谷氨酸被缬氨酸取代。 正因为如此，当缺氧时，血红蛋白能够分解，导致红色的形状变化。 红细胞（RBC），红细胞溶解和无数其他并发症，包括急性和慢性疼痛，慢性 贫血、多系统器官损伤和预期寿命大大缩短。 症状出现后不久出生，当胎儿血红蛋白（HbF）水平下降，并取代 成人镰状血红蛋白由于这一观察结果，已经进行了大量的努力来诱导胎儿血红蛋白 在SCD患者中。不幸的是，唯一一种FDA批准的治疗SCD的药物-- 只有大约50%的服用者有效，其机制尚不清楚。因此，我们的实验室调查 SCD小鼠模型中SCD的替代治疗。 据信，红细胞（RBC）是人体内最常见的细胞。以维持正常 携带氧气和二氧化碳的血红蛋白量，成年人，使超过200万 红血球！这是精心策划的结果成人红细胞生成 起源于骨髓，并遵循从祖细胞到前体细胞再到成熟红细胞的路径。他们 按照原成红细胞的发育方案，然后是嗜碱性成红细胞， 嗜多染性成红细胞，然后是正染性成红细胞。其次是网织红细胞， 这些细胞被去核，失去细胞器，从骨髓迁移到外周循环。 它们通常占所有红细胞的0.5%至1.5%，在贫血的人中，百分比增加。 已发现网织红细胞具有大的空泡内含物，其标记内质网的标记物。 网状体、高尔基体和线粒体。据认为，这些空泡通过胞吐作用消除， 自噬已知PGCα1诱导线粒体自噬和线粒体呼吸的调节剂。最近的研究 在敲除（Nix -/-）小鼠上的研究也证明了线粒体自噬的缺乏导致红细胞寿命短。 来自未经治疗的镰状细胞小鼠的初步数据显示，成熟的红细胞以更高的速率保留线粒体。 水平高于对照组。循环血液中富含线粒体的网织红细胞数量增加可能 促进活性氧水平的升高，改变氧代谢和细胞溶解 在疾病中。 红细胞线粒体增多与SCD相关的分子机制尚不清楚。 通过哺乳动物雷帕霉素靶蛋白（m-TOR）依赖性和非依赖性调节线粒体自噬 线粒体自噬途径这项建议旨在提供试点数据，将异常线粒体自噬与镰状细胞 病理学，并开发新的策略，用于治疗SCD使用线粒体自噬恢复药物。 我们的目标是获得初步的数据，减少红细胞中的线粒体滞留将提供安全的 有效治疗SCD小鼠。