REGULATORY EFFECTS OF HEME TRANSPORT INTO LIVER CELLS

通过血浆蛋白，血凝素，将血红素输送到组织中，如 因为肝脏是一个特定的、受体介导的过程。结果就是这样 肝脏回收血红素，生物有用的铁是保守的， 防止了有毒的血红素的积累和入侵的增长 微生物受到抑制。我们研究的最终目标是：1) 血凝素转运血红素的生化机制 循环中的血红素与最终细胞内的初始结合 亚铁血红素和亚铁血红素的定位以及2)鉴定和表征 血凝素介导的血红素转运的细胞内后果。使用 关于第二个目标，本实验室最近的研究 表明血凝素介导的血红素转运调节基因表达， 包括诱导血红素加氧酶和金属硫蛋白的合成以及 下调转铁蛋白受体的合成。少校 因此，该提案的目标是描述通过哪些机制 血凝素介导的血红素转运到肝细胞刺激 血红素加氧酶和金属硫蛋白的表达。我们尤其会： 1)鉴定和确定特定DNA的作用方式 与血红素-血凝素依赖有关的序列 血红素加氧酶和金属硫蛋白基因的激活 转录； 2)从以下方面表征这些DNA序列元素 其特异的蛋白质结合能力； 3)分离和鉴定相关的DNA结合蛋白 这项规定。

The transport of heme by the plasma protein, hemopexin, into tissues such as the liver is a specific, receptor-mediated process. As a result of this hepatic reclamation of heme, biologically useful iron is conserved, the accumulation of toxic heme is prevented and the growth of invading microorganisms is inhibited. The ultimate goals of our research are 1) to delineate the biochemical mechanism of heme transport by hemopexin - from the initial binding of heme in the circulation to the final intracellular localization of heme and heme-iron - and 2) to identify and characterize the intracellular consequences of hemopexin-mediated heme transport. With regards to this second objective, recent studies in this laboratory indicate that hemopexin-mediated heme transport modulates gene expression, including the induction of heme oxygenase and metallothionein synthesis and down-regulation of the synthesis of the transferrin receptor. The major goal of this proposal then is to characterize the mechanisms by which hemopexin-mediated heme transport into liver cells stimulates the expression of heme oxygenase and metallothionein. In particular, we will: 1) identify and determine the mode of action of specific DNA sequences that are involved in the heme-hemopexin-dependent stimulation of heme oxygenase and metallothionein gene transcription; 2) characterize these DNA sequence elements with respect their specific protein binding capacity; 3) isolate and characterize the DNA-binding proteins involved this regulation.