REGULATION AND FUNCTION OF A HUMAN EMBRYONIC GLOBIN

人类胚胎珠蛋白的调节和功能

• 批准号: 2729732
• 负责人: J ERIC RUSSELL
• 金额: $ 21.37万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2729732
• 关键词: RNase protection assay; disease /disorder model; erythrocytes; gene expression; gene induction /repression; gene targeting; genetic regulation; genetically modified animals; hemoglobin; hemoglobin Ss; hemoprotein biosynthesis; hemoprotein structure; human genetic material tag; human tissue; laboratory mouse; messenger RNA; nuclear runoff assay; oxygen transport; polymerization; posttranscriptional RNA processing; protein structure function; pyrimidines; sickle cell anemia; sickling inhibitor; thalassemia

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.

人epsilon-globin是一种类似β的球蛋白，其表达在发育中仅限于胚胎蛋黄囊的血液岛中的原始红细胞。 与胎儿和成人全球素相反，依得不到依克氏蛋白酶基因调控的机械基础及其编码蛋白的功能知之甚少。 尽管转录下调是胚胎球蛋白基因沉默的主要效应因子，但最近的研究表明，其他转录后事件在此过程中也起着重要且以前意外的作用。涉及的特定转录后机制均未建立，也没有建立它们对Epsilon-Globin调节的最终贡献。 同样，未完整地描述了来自Epsilon-Globin亚基的血红蛋白组装的生理特性。 完全定义Epsilon球蛋白的分子控制和功能的重要性是由于其重新激活的表达可能在治疗上对β-蛋白表达中具有遗传缺陷的成年人有益的可能性。 如果没有对Epsilon-Globin的调节和功能的全面了解，则无法判断这种方法的可行性和临床潜力，目前的建议将提供。 首先，将确定将在表达Epsilon Globin的确定性红细胞组装的血红蛋白中确定关键的生理重要特性。 这些研究将在体外和转基因小鼠中进行，将包括对HBα2epsilon2的O2亲和力的确定以及对β丘脑和镰状细胞贫血患者尤为重要的反踢式特征。 其次，将建立特定的转录后机制对明确红细胞中epsilon球蛋白表达的影响。众所周知，将研究将研究的特定过程（mRNA稳定性，mRNA转化效率和球蛋白亚基稳定性）会影响其他人类球蛋白的表达。 作为一个小组，这些研究将开始使有关胚胎伊普西隆环球蛋白的知识与其他胎儿和成人全球蛋白的了解。 此外，这些研究提供的信息将允许采用旨在Epsilon-Globin重新激活的分子疗法设计的合理方法，以及对这种方法在治疗上有益的可能性的明智期望。