Oxidative stress mechanisms regulating gamma-globin gene transcription in sickle cell disease

镰状细胞病中调节伽马珠蛋白基因转录的氧化应激机制

基本信息

批准号：
10340421
负责人：
Rahima Zennadi
金额：
$ 61.02万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10340421
关键词：
Address Advanced Development Affect Anemia Automobile Driving Bone Marrow Cessation of life Chemicals Chronic Chronic stress Clinical DNA DNA Methylation DNA Modification Process Data Development Dioxygenases Electronic Medical Records and Genomics Network Enzymes Epigenetic Process Erythroblasts Erythrocytes Erythroid Erythropoiesis Event Extramedullary Hematopoiesis FOXO3A gene Fetal Hemoglobin Foundations Functional disorder Gene Expression Gene Expression Regulation Gene Silencing Genes Genetic Transcription Globin Goals Hemolysis Hereditary Disease Histone Acetylation Histone Deacetylase Hypoxia In Vitro Inherited Intervention Knock-out Knowledge MAPK3 gene Mediating Mediator of activation protein Mendelian disorder Messenger RNA Morbidity - disease rate Mus Names Organ Oxidative Stress Pain Pathogenesis Pathway interactions Patients Point Mutation Production Protein translocation Reactive Oxygen Species Regulation Regulator Genes Role Severities Sickle Cell Sickle Cell Anemia Sickle Hemoglobin Splenomegaly Stress Survival Rate Switch Genes Symptoms Untranslated RNA Vascular Diseases beta Globin biological adaptation to stress disease phenotype effective therapy epigenetic regulation fetal reactivity fetus cell gamma Globin gene induction gene repression hematopoietic tissue histone modification improved in vivo insight mouse model novel oxidative damage premature prevent progenitor reduce symptoms sickle erythroid sickling therapeutic target transcription factor vaso-occlusive crisis

项目摘要

Oxidative stress mechanisms regulating g-globin gene transcription in sickle cell disease Abstract: Sickle cell disease (SCD) is the most common inherited monogenic disorder affecting the β-globin gene, leading to the production of sickled-shaped red blood cells (RBCs). Patients with SCD suffer from severe anemia and painful vasoocclusive crises, which are both exacerbated by increased oxidative stress. Induction of normal, but developmentally silenced γ-globin gene of fetal hemoglobin (HbF) expression reduces RBC sickling-mediated vasoocclusion, and anemia, consequently ameliorating clinical severity of SCD. Reducing oxidative stress also improves SCD phenotypic severity. Yet effective treatment options remain limited. Understanding the pathogenesis of the erythroid mechanisms regulating oxidative stress and factors engaged in silencing γ-globin gene, is of substantial value to SCD patients. Our data uncovered an unanticipated role for mediators of oxidative stress in RBC sickling, and in regulating the transcriptional regulatory machinery that represses γ-globin genes as well as epigenetic enzyme components associated with γ-globin to β-globin gene switch in erythroid progenitors. Here, to extend our studies, we will in vitro and in vivo genetically and/or chemically manipulate these mediators of oxidative stress and the regulated pathways using a SCD mouse model, and determine their effects on γ-globin gene regulation, and thus sickling, and their mechanism of action on the transcriptional regulatory machinery that silences γ-globin gene during sickle RBC production. We will also determine the contribution of these mediators in epigenetic DNA and histone modifications associated with γ-globin to β-globin gene switch during sickle RBC production. Because stress erythropoiesis compensates for anemia caused by oxidative damage to the RBCs, we will further validate the effects of these mediators of oxidative stress on stress erythropoiesis in splenic hematopoietic tissue and examine their role in chronic erythroid stress-response, specifically in erythroid terminal maturation and enucleation. We strongly believe that our studies will provide novel and unprecedented insights into the exact mechanisms regulating γ-globin gene silencing and γ-globin to β-globin gene switch in SCD, as well as ineffective erythroid maturation and enucleation. Our long- term goal is to identify remediable sickle erythroid abnormalities to improve SCD pathophysiology. In addition, our studies will lay the foundation for more rational approaches to therapies that better alleviate SCD clinical symptoms.

调节镰状细胞疾病中G-Globin基因转录的氧化应激机制抽象的：镰状细胞病（SCD）是影响β-珠蛋白的最常见的遗传性疾病基因，导致病形的红细胞（RBC）产生。 SCD患者患有严重的贫血和疼痛的血管占性危机，这两者都因氧化增加而加剧压力。诱导胎儿血红蛋白（HBF）的正常但发达的γ-球蛋白基因表达可减少RBC疾病介导的血管结被和贫血，从而改善 SCD的临床严重程度。减少氧化应激还可以改善SCD表型严重程度。然而有效的治疗方案仍然有限。了解红细胞的发病机理调节氧化应激和从事沉默γ-珠蛋白基因的因素是实质性的对SCD患者的价值。我们的数据发现了氧化应激介体在 rbc atchling，并控制反映γ-全基因基因的转录调节机制以及与β-珠蛋白与β-珠蛋白基因开关相关的表观遗传酶成分祖先。在这里，为了扩展我们的研究，我们将在体外和体内一般和/或化学上进行体内使用SCD小鼠模型来操纵这些氧化应激和调节途径的介体，并确定它们对γ-球蛋白基因调节的影响在镰状RBC期间沉默γ-球蛋白基因的转录调节机制的作用生产。我们还将确定这些介体在表观遗传DNA和组蛋白中的贡献与γ-球蛋白相关的修饰在镰状RBC产生期间，到β-珠蛋白基因转换。因为压力红细胞生成补偿由RBC氧化损害引起的贫血，我们将进一步验证这些氧化应激介质对脾脏中应激红细胞生成的影响造血组织并检查其在慢性红系应激反应中的作用，特别是红细胞终末成熟和枚举。我们坚信我们的研究将提供小说对确切机制调节γ-球蛋白基因沉默和γ-球蛋白的前所未有的见解至SCD中的β-珠蛋白基因开关，以及无效的红细胞成熟和枚举。我们的长期术语目标是确定可补充的镰状红细胞异常，以改善SCD病理生理学。在此外，我们的研究将奠定基础，以实现更好的疗法方法减轻SCD临床症状。