REGULATION AND FUNCTION OF A HUMAN EMBRYONIC GLOBIN

人ε-珠蛋白是一种β-样珠蛋白，其表达在胚胎卵黄囊的血岛中发育受限于原始成红细胞。 与胎儿和成人球蛋白相反，ε-球蛋白基因调控的机制基础及其编码蛋白的功能知之甚少。 虽然转录下调是胚胎珠蛋白基因沉默的主要效应子，但最近的研究表明，其他转录后事件在这一过程中也起着重要的和以前未预料到的作用。既没有具体的转录后机制，也没有最终的贡献ε-珠蛋白的调节已经建立。 同样，由ε-珠蛋白亚基组装的血红蛋白的生理特性也没有完全描述。 充分确定β-珠蛋白的分子控制和功能的重要性被其重新激活的表达可能对β-珠蛋白表达中具有遗传缺陷的成人具有治疗益处的可能性放大。 如果不全面了解ε-珠蛋白的调节和功能，就不能判断这种方法的可行性和临床潜力，而目前的建议将提供。 首先，将确定血红蛋白的关键生理学重要特性，这些血红蛋白将在表达α珠蛋白的定形红细胞中组装。 这些研究将在体外和转基因小鼠中进行，将包括确定O2亲和力和Hb α 2 ε 2的抗镰状化特性，这对β地中海贫血和镰状细胞贫血患者特别重要。 其次，将建立特定的转录后机制对定形红细胞中α珠蛋白表达的影响。将研究的特定过程（mRNA稳定性、mRNA翻译效率和球蛋白亚基稳定性等）已知会影响其他人球蛋白的表达。 作为一个整体，这些研究将开始使我们对胚胎β球蛋白的了解与对其他胎儿和成人球蛋白的了解达到同等水平。 此外，这些研究提供的信息将允许设计旨在ε-珠蛋白再活化的分子疗法的合理方法，以及对这种方法在治疗上有益的可能性的知情预期。

Human epsilon-globin is a beta-like globin whose expression is developmentally restricted to primitive erythroblasts in the blood islands of the embryonic yolk sac. In contrast to fetal and adult globins, the mechanistic bases for epsilon-globin gene regulation and the function of its encoded protein are poorly understood. Although transcriptional downregulation is a major effector of embryonic globin gene silencing, recent studies indicate that other, post-transcriptional events also play an important and previously unanticipated role in this process. Neither the specific post-transcriptional mechanisms involved, nor their ultimate contribution to epsilon-globin regulation have been established. Likewise, the physiologic properties of hemoglobins assembling from epsilon-globin subunits are incompletely described. The importance of fully defining the molecular controls and function of epsilon globin is magnified by the possibility that its reactivated expression might be therapeutically beneficial to adults with genetic defects in beta-globin expression. The feasibility and clinical potential of this approach cannot be judged without a comprehensive understanding of epsilon-globin regulation and function, which the current proposal will provide. First, key physiologically-important properties will be determined for hemoglobins that will assemble in definitive erythrocytes expressing epsilon globin. These studies, which will be done both in vitro and in transgenic mice, will include determinations of the O2 affinity and the anti-sickling characteristics of Hb alpha2epsilon2, of particular importance to individuals with beta thalassemia and sickle cell anemia. Second, the effect of specific post-transcriptional mechanisms on the expression of epsilon globin in definitive erythrocytes will be established. The specific processes that will be studied (mRNA stability, mRNA translational efficiency, and globin subunit stability, among others) are known to affect the expression of other human globins. As a group, these studies will begin to bring what is known about embryonic epsilon globin into parity with what is known about other fetal and adult globins. Moreover, the information provided by these studies will permit a reasoned approach to the design of molecular therapies aimed at epsilon-globin reactivation as well as an informed expectation of the likelihood that such an approach will be therapeutically beneficial.