Pharmacological Control Of Human Hemoglobin Gene Expression

人血红蛋白基因表达的药理学控制

• 批准号: 9148737
• 负责人: Alan Schechter
• 金额: $ 12.17万
• 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/9148737
• 关键词: Adhesives; Affect; Annual Reports; Blood Circulation; Blood Vessels; CD34 gene; Cells; Child; Clinical; Clinical Data; Clinical Research; Complex; Cyclic GMP; Development; Developmental Biology; Disease; Erythroid; Erythroid Cells; Fetal Hemoglobin; Functional disorder; Gene Expression; Genes; Globin; Growth; Hematopoietic; Hemoglobin; Hereditary Disease; Human; Impairment; Ions; MAP Kinase Gene; Measures; Metabolism; Molecular Genetics; Nitric Oxide; Nitrites; Organ; Pain; Pathology; Pathway interactions; Patients; Perception; Peripheral Nervous System; Phenotype; Process; Property; Proto-Oncogene Proteins c-akt; Publishing; Reporting; Research; Reticulocytes; Reticulocytosis; Severity of illness; Sickle Cell; Sickle Cell Anemia; Signal Transduction; Syndrome; System; Thalassemia; Therapeutic; United States National Institutes of Health; Work; biophysical analysis; gamma Globin; hydroxyurea; infancy; interest; mTOR Signaling Pathway; mortality; novel strategies; polymerization; response; transcription factor

The ontogeny of the human globin genes is an important focus of study both with respect to the fundamental developmental biology and molecular genetics of the control of expression of this complex gene system, but also because modifying this developmental control would be of therapeutic value in the treatment of the prevalent genetic diseases of hemoglobin, such as sickle cell anemia and thalassemia. This has been one of our research emphases for more than 25 years. Among other findings was our demonstration that hydroxyurea, now approved to treat sickle cell anemia by elevating fetal hemoglobin, affects intracellular nitric oxide metabolism, specifically changing cyclic GMP levels. These results brought together our NO (see Annual Reports DK025093 and DK025104) and our sickle cell work and has led us to continue gene expression studies in human hematopoietic cells in collaborative studies. One such study shows that many transcription factors change during ontogeny of human CD34+ erythroid cells in culture, especially related to the JAK-STAT and AKT pathways. In more recent studies, just published, we showed that CD 34+ cells have increased levels of gene expression of the PI3/AKT and MAPK genes related to the mTOR signaling pathways as compared to other hematopoietic cells. We have recently reported that high levels of reticulocytosis in early infancy in children with sickle cell anemia is correlated with a subsequent more severe clinical course and have planned studies to see if this relates to adhesive properties of these reticulocytes. We have also helped analyze clinical data from the large number of sickle cell patients followed at NIH and showed that increases of fetal hemoglobin correlates well with apparent benefit-as measured by organ pathology or mortality-from hydroxyurea therapy. Our long interest in understanding the pain phenotype in these patients has resulted in analyses which suggest that there are both central and peripheral nervous system aspects to perception of pain.

人类珠蛋白基因的个体发育是控制这一复杂基因系统表达的基础发育生物学和分子遗传学的重要研究重点，也是因为修改这一发育调控机制将在治疗常见的血红蛋白遗传性疾病，如镰状细胞性贫血和地中海贫血方面具有治疗价值。这是我们25年多来的研究重点之一。在其他发现中，我们证明了羟基脲，现在被批准通过提高胎儿血红蛋白来治疗镰状细胞性贫血，影响细胞内的一氧化氮代谢，特别是改变循环GMP水平。这些结果将我们的NO(见年度报告DK025093和DK025104)和我们的镰刀细胞工作结合在一起，并引导我们继续合作研究人类造血细胞的基因表达。一项这样的研究表明，在培养的人CD34+红系细胞的个体发育过程中，许多转录因子发生了变化，特别是与JAK-STAT和AKT通路有关。在最近发表的研究中，我们发现CD34+细胞与其他造血细胞相比，与mTOR信号通路相关的PI3/AKT和MAPK基因表达水平升高。我们最近报道，镰状细胞性贫血儿童早期高水平的网织红细胞增多与随后更严重的临床病程相关，并计划进行研究，以确定这是否与这些网织红细胞的黏附特性有关。我们还帮助分析了NIH追踪的大量镰状细胞患者的临床数据，结果表明，胎儿血红蛋白的增加与羟基尿素治疗的明显益处--以器官病理或死亡率衡量--有很好的相关性。我们对了解这些患者的疼痛表型的长期兴趣导致了分析表明，疼痛的感知既有中枢神经系统的方面，也有外周神经系统的方面。