INDUCTION OF HEME BIOSYNTHESIS IN FRIEND CELLS

本研究有两个主要的长期目标， 实验室 其中第一个是充分描述终端三 血红素生物合成途径的膜相关酶。 这 表征包括基础生物化学研究和 它们的生物合成和转运的机制和调控 线粒体内膜 第二个主要目标是描述现有的监管机制 在红系和非红系细胞的血红素生物合成途径中 类型 人们希望，通过界定发生的事件的性质， 正常细胞，这将有可能得到更好的理解为什么 在血红素生物合成机制中具有遗传损伤的个体 （卟啉）显示变量的性状的突变率。 本提案中的具体实验旨在解决这些问题 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）继续描述 调节末端三种酶的时间合成， 红系细胞分化，2）检测所提出的细胞分化， 调节血红素池; 3）ALA的生化和分子检测 合成酶的研究，以及4）检测两种ALA的调节和作用 红系和非红系细胞中的淀粉酶。 在所有这些实验中 培养的小鼠红白血病（MEL）细胞，通过 DMSO被用作红系细胞模型，而培养的小鼠肝癌 细胞（Hepa 1c 1c 7）用作非红系细胞模型。 从这些研究中获得的数据将作为 临床竞技场的研究人员，他们关注的是医学疾病， 血红素生物合成（卟啉症和贫血）和红细胞生物合成 （白血病）。 此外，这些研究对毒理学家也有价值。 谁的目标物质对细胞血红素代谢有影响。

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.