ABNORMAL HEMOGLOBIN SYNTHESIS-MECHANISM & DETECTION

本研究提案涉及对 血红蛋白病和地中海贫血。 它将 重点抓好四个方面： (1)继续发展β-内酰胺酶产前诊断方法 地中海贫血DNA分析 在过去的几年里，直接的方法， 应用DNA技术产前诊断α地中海贫血和镰状细胞贫血 分析已经到位。 导致贝塔的分子损伤 地中海贫血是多种多样的，因此，重要的是要确定类型 特定区域的突变。 有了这些知识， 产前诊断是可以设计的。 诊断的实施 通过DNA分析将提高测试的安全性和准确性。 (2)的 导致地中海贫血突变的分子病变将继续存在， 表征了 这些研究可能会进一步了解控制 珠蛋白基因的表达。 获得不明β地中海贫血基因 在（1）中的工作将被表征。 有趣的突变， 可以提供洞察珠蛋白合成的控制，和自发的 还将研究突变。 (3)转基因小鼠模型将 用于研究人类珠蛋白基因表达的调控。 该模型可 为研究组织特异性和发育控制提供了一种手段， 人珠蛋白基因表达。 (4)使用抑制性tRNA作为手段 克服β地中海贫血无义突变的方法 研究了 插入赖氨酸或谷氨酰胺的人类抑制性tRNA基因 将被引入来自患者的红系细胞中 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.