INDUCTION OF HEME BIOSYNTHESIS

本研究有两个主要的长期目标， 实验室 其中第一个是在生物化学和 分子水平上血红素生物合成途径的末端酶， 第二是研究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。 工作的构成部分 这些目标之一是在生物化学和细胞水平上了解 两种人类卟啉症的具体性质，杂色卟啉症（VP）和 红细胞生成性原卟啉症（EPP）和X连锁疾病 铁粒幼细胞性贫血 目前的研究建议可细分为三大领域; I）基因敲除和基因置换的产生和表征 在培养的小鼠ES细胞中，II） 相应的遗传修饰小鼠，和III）表征 哺乳动物ALA合酶。 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表现出可变的抑郁症， 为什么有症状的患者表现出显著不同的 症状，以及为什么临床记录的差异存在于男性和 女性患者。 我们对X连锁铁粒幼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，并观察 如果杂合子女性受损，如果纯合子女性受损， 可行的 对ALA合酶的表征的兴趣在于理解在一个特定的水平上， 生化水平的性质酶的缺陷，人们发现在X- 相关铁粒幼细胞性贫血，并更好地了解这种酶， 血红素生物合成的关键调控点之一。

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.