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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：
10649412
负责人：
Rahima Zennadi
金额：
$ 58.66万
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/10649412
关键词：
Address Advanced Development Affect Anemia Automobile Driving Bone Marrow Cessation of life Chemicals Chronic Chronic stress Clinical Compensation 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 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 Repression Role Severities Shapes 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 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 theories 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.

镰状细胞病中调节g-珠蛋白基因转录的氧化应激机制