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: 8741364
• 负责人: Constance Noguchi
• 金额: $ 44.74万
• 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/8741364
• 关键词: Affect; Anemia; Blood Glucose; Cell Survival; Cells; Chronic Kidney Failure; Data; Diet; Dose; Erythrocytes; Erythroid; Erythroid Progenitor Cells; Erythropoiesis; Erythropoietin; Erythropoietin Receptor; Fatty acid glycerol esters; Fetal Hemoglobin; Gene Expression; Genes; Globin; Glucose; Goals; Hematocrit procedure; Hemoglobin; Homeostasis; Human; Hypoxia; Kidney; Metabolic; Metabolism; Mus; Oxygen measurement, partial pressure, arterial; Patients; Production; Saline; Sickle Cell Anemia; Thalassemia; Therapeutic; beta Globin; erythroid differentiation; fasting blood glucose level; feeding; gamma Globin; glucose uptake; hematopoietic tissue; human GATA1 protein; interstitial cell; peripheral blood; premature; programs; receptor expression; response; transcription factor

Erythropoietin is known for its activity in stimulating erythroid progenitor cell survival, proliferation and differentiation. Erythropoietin is produced in the interstitial cells of the kidney in a hypoxic responsive manner and is used in treatment of anemia in patients with chronic kidney disease. High dose erythropoietin treatment in mice resulted in reduced blood glucose level in addition to increased hematocrit, suggesting that erythropoietin may affect metabolic homeostasis. Erythropoietin treatment decreased fasting blood glucose level in both normal diet fed mice and high fat diet fed mice, compared with mice treated with saline. Since hematopoietic tissue is the major target of erythropoietin, we speculate that erythropoietin may stimulate glucose uptake in hematopoietic tissue, especially during erythroipoiesis. We examined cultures of human erythroid progenitor cells isolated from peripheral blood and found that glucose uptake per cell increased with erythroid differentiation and peaked in late erythroid progenitor cells, then decreased during terminal differentiation. Glucose uptake appeared to follow erythropoietin receptor expression and was maximal when erythropoietin receptor levels were highest; glucose uptake decreased as erythropoietin receptor levels decreased with the progression of erythroid maturation to mature erythrocytes that no longer express erythropoietin receptor. No induction of gamma-globin gene expression was observed. The combination of erythropoietin with elevated glucose resulted in a transient increase in gamma-globin gene expression and increased hemoglobinization. While this activity of elevated glucose level in combination with EPO affects the erythroid differentiation program, change in the resultant gamma/(gamma + beta) globin ratio is minimal by the end of the culture period. These data suggest that high dose glucose during erythropoietin stimulated erythroid differentiation results in premature hemoglobin accumulation and differentiation with no great change in proportion of fetal hemoglobin production.

促红细胞生成素以其在刺激红细胞祖细胞存活，增殖和分化的活性而闻名。 促红细胞生成素以低氧反应方式在肾脏的间隙细胞中产生，用于治疗慢性肾脏疾病患者的贫血。高剂量红细胞生成素治疗在小鼠中还导致血糖水平降低，除血细胞比容升高外，表明促红细胞生成素可能影响代谢稳态。与用盐水治疗的小鼠相比，红细胞生成素治疗在正常饮食喂养的小鼠和高脂肪饮食喂养小鼠中降低了空腹血糖水平。由于造血组织是促红细胞生成素的主要靶标，因此我们推测促红细胞生成素可能刺激造血组织中的葡萄糖摄取，尤其是在红细胞脂蛋白期间。我们检查了从外周血分离出的人红细胞祖细胞的培养物，发现每个细胞的葡萄糖摄取随红细胞分化而增加，并在促红色祖细胞中达到峰值，然后在终末分化过程中降低。葡萄糖摄取似乎遵循促红细胞生成素受体的表达，当红细胞生成素受体水平最高时，葡萄糖的摄取量最大。随着促红细胞生成素受体水平的降低，葡萄糖的摄取随着红细胞的成熟到不再表达红细胞生成素受体的成熟红细胞的发展而降低。未观察到γ-球蛋白基因表达的诱导。红细胞生成素与葡萄糖升高的组合导致γ-球蛋白基因表达和血红蛋白增加的瞬时增加。尽管升高的葡萄糖水平与EPO的活性影响了红细胞分化程序，但到达培养期结束时，所得的伽马/（伽马 +β）球蛋白比的变化很小。这些数据表明，红细胞生成素期间的高剂量葡萄糖刺激红细胞分化导致早产血红蛋白的积累和分化，而胎儿血红蛋白产生的比例没有很大变化。