ABNORMAL HEMOGLOBIN SYNTHESIS-MECHANISM & DETECTION

这项研究建议涉及到对 在分子水平上的血红蛋白病和地中海贫血。会的 集中力量抓好四个方面： (1)继续开发Beta产前诊断方法 DNA分析显示为地中海贫血。在过去的几年里，直接的方法 α-地中海贫血和镰状细胞性贫血的DNA产前诊断 分析已经变得可用。贝塔病毒致病的分子病变 地中海贫血是多种多样的，因此确定其类型很重要 某一特定区域存在突变的可能性。有了这些知识，具体的方法 可以设计出一套产前诊断系统。诊断法的实施 通过DNA分析将提高检测的安全性和准确性。(2) 导致地中海贫血突变的分子损伤将继续存在 特色化的。这样的研究可能会加深我们对控制的理解 珠蛋白基因的表达。获得未知的贝塔地中海贫血基因 来自(1)中的工作将被刻画。有趣的突变 可以提供对珠蛋白合成的控制和自发的洞察 突变也将被研究。(3)转基因小鼠模型 用于研究人类珠蛋白基因表达的调控。该型号可能 提供了一种研究组织特异性和发育控制的方法 人类珠蛋白基因的表达。(4)使用抑制tRNAs作为手段 克服贝塔地中海贫血的无义突变将是 调查过了。插入赖氨酸或谷氨酰胺的人抑制tRNA基因 进入UAG密码子将被引入患者的红系细胞 带有Beta17无义突变和Beta39无义突变。

This research proposal deals with the continued investigation of the hemoglobinopathies and thalassemia on a molecular level. It will concentrate on four areas: (1) Continued development of approaches to prenatal diagnosis for Beta thalassemia by DNA analysis. During the past few years, direct methods of prenatal diagnosis of Alpha thalassemia and sickle cell anemia by DNA analysis have become available. The molecular lesions responsible for Beta thalassemia are diverse and it is therefore important to determine the type of mutation present in a given area. With this knowledge, specific methods of prenatal diagnosis could be designed. The implementation of diagnosis by DNA analysis will improve the safety and accuracy of the test. (2) The molecular lesions causing the thalassemia mutations will continue to be characterized. Such studies may further our understanding of the control of globin gene expression. Unidentified Beta thalassemia genes obtained from the work in (1) will be characterized. Interesting mutations which may provide insight into the control of globin synthesis, and spontaneous mutations will also be studied. (3) The transgenic mouse model will be used to study regulation of human globin gene expression. This model may provide a means for studying tissue-specific and developmental controls of human globin gene expression. (4) The use of suppressor tRNAs as a means of overcoming the nonsense mutation in Beta thalassemia will be investigated. Human suppressor tRNA genes that insert lysine or glutamine into the UAG codon will be introduced into erythroid cells from patients with the Beta17 nonsense and Beta39 nonsense mutations.