INDUCTION OF HEME BIOSYNTHESIS

这项研究有两个主要的长期目标 实验室。首先是在生物化学和生物化学方面的特征 在分子水平上，血红素生物合成途径的末端酶和 第二个是研究血红素生物合成的调节机制， 存在于红系和非红系细胞类型中。两者不可分割的一部分 这些目标中的一个是在生化和细胞水平上理解 人类两种卟啉症的特殊性质，杂色卟啉症(VP)和 红细胞生成性原红细胞增多症(EPP)与X连锁疾病 铁粒母细胞性贫血。 目前的研究建议可以细分为三个一般领域； 一)基因敲除和基因替换的生产和特征 在培养的小鼠ES细胞中，II)产生和初步鉴定 相应的转基因小鼠，以及iii)表征 哺乳动物丙氨酸合成酶。我们在建立 卟啉细胞和动物模型是为了了解为什么 患有这些疾病的人通常会表现出不同的外显能力， 为什么有症状的患者表现出显著不同的强度 症状，以及为什么临床记录的男性和 女性患者。我们对X连锁铁粒母细胞性贫血的兴趣是 确定这种疾病对正常红细胞生成的影响，并查看 如果杂合子雌性受到损害，如果纯合子雌性受到损害 可行。 对丙氨酸合成酶特性的兴趣在于了解 生化水平在X-细胞中发现的酶缺陷的性质 为了更好地了解这种酶，这种酶是 是血红素生物合成的关键调节点之一。

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.