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INDUCTION OF HEME BIOSYNTHESIS

血红素生物合成的诱导

基本信息

批准号：
2701069
负责人：
HARRY A DAILEY
金额：
$ 19.04万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
1987
资助国家：
美国
起止时间：
1987-05-01 至 2000-04-30
项目状态：
已结题

项目摘要

There are two major long range goals for the research carried out in this laboratory. The first of these is to characterize at the biochemical and molecular level the terminal enzymes of the heme biosynthetic pathway and the second is to examine regulatory mechanisms of heme biosynthesis that exist in erythroid and non-erythroid cell types. An integral part of both of these goals is to understand at both a biochemical and cellular level the specific nature of two human porphyrias, variegate porphyria (VP) and erythropoietic protoporphyria (EPP), and the disease X-linked sideroblastic anemia. The current research proposal can be subdivided into three general areas; I) production and characterization of gene knockout and gene replacements in cultured mouse ES cells, II) production and initial characterization of the corresponding genetically modified mice, and III) characterization of mammalian ALA synthase. Our specific interests in establishing the porphyric cell and animal models are to gain an understanding of why humans possessing these disorders routinely exhibit variable penetrance, why symptomatic patients exhibit significantly different intensities of symptoms, and why clinically documented differences exist between male and female patients. Our interest in the X-linked sideroblastic anemia is to determine the effect of this disorder on normal erythropoiesis, and to see if the heterozygous female is compromised, and if the homozygous female is viable. The interest in characterization of ALA synthase is to understand at a biochemical level the nature of the enzymatic defects that one finds in X- linked sideroblastic anemia and to better understand this enzyme which is one of the key regulatory points in heme biosynthesis.

本研究有两个主要的长期目标实验室。第一个是表征生化和分子水平上血红素生物合成途径的末端酶和第二个是检查血红素生物合成的调节机制存在于红细胞和非红细胞类型中。两者不可分割的一部分这些目标之一是在生化和细胞水平上理解两种人类卟啉症的特殊性质：杂色卟啉症 (VP) 和红细胞生成性原卟啉症 (EPP) 和 X 连锁疾病铁粒幼细胞贫血。当前的研究提案可以分为三个一般领域； I) 基因敲除和基因替换的产生和表征在培养的小鼠 ES 细胞中，II) 的生产和初步表征相应的转基因小鼠，以及 III) 的表征哺乳动物 ALA 合酶。我们对建立卟啉细胞和动物模型是为了了解原因患有这些疾病的人通常表现出不同的外显率，为什么有症状的患者表现出明显不同的强度症状，以及为什么临床记录的男性和女性之间存在差异女性患者。我们对 X 连锁铁粒幼细胞贫血的兴趣是确定这种疾病对正常红细胞生成的影响，并观察如果杂合女性受到损害，并且如果纯合女性受到损害可行的。对 ALA 合酶表征的兴趣在于了解生化水平 X- 中发现的酶缺陷的性质与铁粒幼细胞贫血相关并更好地了解这种酶血红素生物合成的关键调节点之一。