Pharmacological Control Of Human Hemoglobin Gene Expression

人类珠蛋白基因的个体发生是一个重要的研究焦点，无论是在基础发育生物学方面，还是在控制这一复杂基因系统表达的分子遗传学方面，而且还因为修改这种发育控制将在治疗常见的血红蛋白遗传疾病，如镰状细胞性贫血和地中海贫血中具有治疗价值。这是我们25年来的研究重点之一。在其他研究结果中，我们证明羟基脲，现在被批准通过提高胎儿血红蛋白治疗镰状细胞性贫血，影响细胞内一氧化氮代谢，特别是改变环GMP水平。这些结果将我们的NO（见年度报告DK025093和DK025104）和我们的镰状细胞工作结合在一起，并引导我们在合作研究中继续进行人类造血细胞的基因表达研究。其中一项研究表明，在培养的人CD34+红细胞的个体发育过程中，许多转录因子发生了变化，尤其是与JAK-STAT和AKT通路相关的转录因子。在最近发表的研究中，我们发现与其他造血细胞相比，cd34 +细胞中与mTOR信号通路相关的PI3/AKT和MAPK基因表达水平升高。我们最近报道了镰状细胞性贫血儿童婴儿期高水平的网状细胞缺血症与随后更严重的临床病程相关，并计划研究这是否与这些网状细胞的粘附特性有关。我们还帮助分析了在NIH跟踪的大量镰状细胞患者的临床数据，并表明胎儿血红蛋白的增加与羟基脲治疗的明显益处（通过器官病理或死亡率来衡量）密切相关。我们对了解这些患者的疼痛表型的长期兴趣导致分析表明，中枢和外周神经系统方面都有疼痛的感知。

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.