REGULATORY EFFECTS OF HEME TRANSPORT INTO LIVER CELLS

血红素通过血浆蛋白，血红素结合蛋白，转运到组织中， 因为肝脏是一个特定的受体介导的过程。 由于这种 肝脏回收血红素，生物学上有用的铁是保守的， 有毒血红素的积累被阻止， 微生物被抑制。 我们研究的最终目标是：（1） 阐明血红素结合蛋白转运血红素的生化机制 血红素在循环中的初始结合到最终的细胞内 血红素和血红素铁的定位-和2）识别和表征 血红素蛋白介导的血红素转运的细胞内后果。 与 关于第二个目标，这个实验室最近的研究 表明血红素蛋白介导血红素转运调节基因表达， 包括血红素加氧酶和金属硫蛋白合成的诱导， 下调转铁蛋白受体的合成。 主要 本提案的目的是描述 血红素蛋白介导的血红素向肝细胞的转运刺激了 血红素氧合酶和金属硫蛋白的表达。 我们尤其会： 第一章 识别和确定特定DNA的作用模式 参与血红素-血红素结合蛋白依赖性 血红素加氧酶和金属硫蛋白基因刺激 转录; （二） 描述这些DNA序列元件， 其特异性蛋白结合能力; 第三章 分离并鉴定所涉及的DNA结合蛋白 这个规定。

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.