INDUCTION OF HEME BIOSYNTHESIS IN FRIEND CELLS

这项研究有两个主要的长期目标 实验室。其中第一个是全面描述三号航站楼的特征 血红素生物合成途径的膜相关酶。这 表征包括基础生化研究和检测 它们的生物合成和转运到细胞的机制和调控 线粒体膜内层。 第二个主要目标是描述现有监管机制的特点 在红系和非红系细胞中的血红素生物合成途径 类型。希望通过定义在中发生的事件的性质 正常细胞，就有可能更好地理解为什么 在血红素生物合成机制中有遗传损害的个体 (卟啉症)表现出不同的特征外显率。 本提案中的具体实验旨在接近这些 通过几种不同的途径实现两个总体目标。这些可以广泛地 分为四类：1)继续刻画 末端三种酶的时间合成调控 红系细胞分化，2)建议细胞的检查 调节血红素库，3)ALA生化和分子检测 合酶，以及4)两种丙氨酸的调节和作用的研究 红系和非红系细胞中的合酶。在所有这些实验中 丹参对体外培养的小鼠红白血病细胞的诱导分化作用 DMSO作为红系细胞模型，而培养的小鼠肝癌 细胞(HEPA 1c1c7)作为非红系细胞模型。 从这些研究中获得的数据将作为 临床领域的研究人员，他们关心的是医疗疾病 血红素生物合成与红细胞生物发生 (白血病)。此外，这些研究应该对毒物学家有价值。 世卫组织靶标物质对细胞内的血红素代谢有影响。

There are two major long range goals for the research carried out in this laboratory. The first of these is to fully characterize the terminal three membrane associated enzymes of the heme biosynthetic pathway. This characterization includes both basic biochemical studies and examination of the mechanism and regulation of their biosynthesis and translocation to the inner mitochondrial membrane. The second major goal is to characterize regulatory mechanisms that exist in the heme biosynthetic pathway in both erythroid and nonerythroid cell types. It is hoped that by defining the nature of the events that occur in normal cells, it will be possible to get a better understanding of why individuals with genetic lesions in the heme biosynthetic machinery (porphyrias) show variable penetrance of the traits. The specific experiments in this proposal are designed to approach these two general goals via several different avenues. These can be broadly grouped into four categories: 1) continued characterization of the regulation of the temporal synthesis of the terminal three enzymes during erythroid cell differentiation, 2) examination of the proposed cellular regulatory heme pool, 3) biochemical and molecular examination of ALA synthase, and 4) examination of the regulation and roles of the two ALA synthases in erythroid and nonerythroid cells. In all of these experiments cultured murine erythroleukemia (MEL) cells induced to differentiate by DMSO are used as an erythroid cell model, while cultured mouse hepatoma cells (Hepa 1c1c7) are employed as a non-erythroid cell model. The data obtained form these studies will serve as a foundation for researchers in the clinical arena whose concerns are the medical disorders of heme biosynthesis (the porphyrias and anemias) and red cell biogenesis (leukemias). In addition these studies should be of value to toxicologists who target substances have an affect on cellular heme metabolism.