Regulation of Fetal Hemoglobin Production in Humans.

摘要：出生前后胎儿血红蛋白表达降低是镰状细胞和地中海贫血综合征临床表现的决定性机制。因此，预防或逆转这一过程是治疗这些疾病的主要临床目标。实验室正在进行的一项研究包括信号转导级联反应和红细胞的生长，作为增加成人胎儿血红蛋白水平的方法。在这种情况下，我们开发了一种标准的实验分析，从正常志愿者和血红蛋白病患者中获得培养的人红细胞祖细胞，以确定在成人红细胞生成过程中能够调节红细胞生长和胎儿血红蛋白生成的细胞因子。干细胞因子（SCF）被认为对红细胞生长和胎儿血红蛋白的产生有显著影响，甚至在有犯罪倾向的原红细胞中也是如此。这种方法导致发现tgf - β， SCF和促红细胞生成素协同作用以增加胎儿血红蛋白的产生。这些增加是泛细胞的，并导致HbF的产生达到足以逆转体内镰状表型的水平。人们已经开始努力确定细胞因子作用的分子机制，并利用血红蛋白病患者的临床样本在体内将这些发现联系起来。

Summary: Decreased expression of fetal hemoglobin around the time of birth represents the defining mechanism in the clinical manifestation of sickle-cell and beta-thalassemia syndromes. Therefore, prevention or reversal of that process represents a major clinical goal for the treatment of those diseases. An ongoing interest of the laboratory involves the study of signal transduction cascades and growth among fully committed erythroid cells as a method of increasing levels of fetal hemoglobin in adult humans. In this context, we developed a standard experimental assay of cultured human erythroid progenitor cells obtained from normal volunteers as well as patients with hemoglobinopathies to identify cytokines capable of modulating erythroid growth and fetal hemoglobin production during adult erythropoiesis. Stem cell factor (SCF) was identified as having significant effects upon erythroid growth and fetal hemoglobin production even among committed proerythroblasts. That approach led to the discovery that TGF-beta, SCF and Erythropoietin act in concert to increase fetal hemoglobin production. Those increases were pancellular, and resulted in production of HbF to levels that may be sufficient to reverse the sickle phenotype in vivo. Efforts have begun to determine the molecular mechanisms responsible for the cytokine effects and to correlate those findings in vivo using clinical samples from patients with hemoglobinopathies.