Globin Gene Expression And Treatment Of Sickle Cell Anemia

球蛋白基因表达和镰状细胞性贫血的治疗

• 批准号: 8157965
• 负责人: Constance Noguchi
• 金额: $ 35.17万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8157965
• 关键词: Adult; Binding; Erythroid; Erythroid Progenitor Cells; Erythropoiesis; Erythropoietin; Fetal Hemoglobin; Gene Expression; Gene Transfer; Globin; Sickle Cell Anemia; gamma Globin; human GATA1 protein

Erythroid differentiation of adult hematopoietic progenitor cells requires stimulation by erythropoietin (Epo), a hypoxia inducible cytokine that promotes erythroid progenitor cell survival, proliferation, differentiation and Hb production. Epo binds to its cell surface receptor and induces transcription factors that regulate erythroid gene expression such as the general erythroid factor GATA-1, the basic helix-loop-helix transcription factor, Tal1, and EKLF which is relatively specific for beta-globin expression. Epo stimulation also increases expression of its own receptor resulting in creased Epo sensitivity and response. Gamma-globin is preferentially expressed during early erythropoiesis while beta-globin expression increases with induction of EKLF. Induction of Epo receptor expression is directly linked to the increase in erythroid transcription factor expression and is mediated through corresponding binding motifs in the EPO receptor proximal promoter and downstream region flanking the transcription start site. Over expression of EPO receptor further increases erythroid transcription factor expression, globin gene transcription and erythroid differentiation. Therefore, manipulation of Epo response by direct manipulation of Epo receptor expression or Epo signaling may alter the relative expression of gamma-globin and beta-globin and the overall production of fetal hemoglobin.

成人造血祖细胞的红细胞分化需要红细胞生成素（EPO）刺激，这是一种诱导的缺氧细胞因子，可促进红细胞祖细胞的存活，增殖，分化和HB产生。 EPO与其细胞表面受体结合，并诱导转录因子，这些转录因子调节红斑基因表达，例如一般的红系因因子GATA-1，基本的Helix-loop--螺旋转录因子，TAL1和EKLF，对于β-蛋白表达而言相对特异性。 EPO刺激还​​增加了其自身受体的表达，从而导致EPO敏感性和反应。 γ-球蛋白在红细胞生成早期优先表达，而β-珠蛋白表达随着EKLF的诱导而增加。 EPO受体表达的诱导直接与红斑转录因子表达的增加有关，并通过EPO受体近端启动子和下游区域的相应结合基序与转录起始位点两侧介导。 EPO受体的表达进一步增加了红系转录因子表达，球蛋白基因转录和红系分化。因此，通过直接操纵EPO受体表达或EPO信号传导来操纵EPO响应可能会改变γ-球蛋白和β-珠蛋白的相对表达以及胎儿血红蛋白的总体产生。