REGULATORY EFFECTS OF HEME TRANSPORT INTO LIVER CELLS

描述：血红素结合素是一种血浆糖蛋白，可将血红素转运至肝脏 细胞通过特定的受体介导的过程。 血红素加氧酶a 微粒体膜酶，催化的初始和限速步骤， 血红素降解 血红素释放的铁分子沉积在 铁蛋白簇。 这些蛋白质的协同作用使得 保护生物有用的铁，防止有毒物质的积累， 血红素分子并抑制入侵微生物的生长。 的 我们研究的长期目标是更好地了解 血红素和铁代谢，特别强调血红素结合蛋白的作用 血红素氧合酶在维持血红素和铁稳态的不利条件下 条件（例如，在由于遗传性疾病引起的血管内溶血期间 和/或细菌或病毒感染或细胞应激， 环境毒素）。 这项研究计划的一个方面是， 血红素加氧酶基因作用机制的生化表征 激活反应的底物血红素和应力相关的代理商。 血红素对血红素加氧酶的调节是目前研究的重点。 这一提案的具体目标是， 自上次竞争性会议以来， 综述，1）定义最小血红素反应元件（HRE）， 突变分析：功能和蛋白质结合研究。 2)以隔离 并表征HRE结合蛋白（HRE-BP）及其相应的 cDNA克隆。 3)为了确定哪些HRE-BP介导血红素反应性， 特异性HRE-BP表达的抑制（即，识别 血红素反应因子）。 血红素和血红素加氧酶的其他诱导剂的共同特征是， 它们产生细胞内氧化应激。 由于促氧化剂（或 氧化状态）与多种人类病理学有关 包括动脉粥样硬化、缺血/再氧合、损伤和癌症， 目前的研究结果应该进一步加深我们对基本的认识， 这些疾病的生物学。

DESCRIPTION: Hemopexin, a plasma glycoprotein, transports heme into liver cells by a specific, receptor-mediated process. Heme oxygenase, a microsomal membrane enzyme, catalyzes the initial and rate-limiting step in heme degradation. The iron molecule released from heme is deposited on ferritin clusters. The concerted action of these proteins permits conservation of biologically useful iron, prevents accumulation of toxic heme molecules and inhibits the growth of invading microorganisms. The long-term objective of our research is to better understand the processes of heme and iron metabolism, with particular emphasis on the role of hemopexin and heme oxygenase in maintaining heme and iron homeostasis under adverse conditions (e.g., during intravascular hemolysis due to hereditary disorders and/or bacterial or viral infections or cellular stress caused by environmental toxins). One aspect of this research program is the biochemical characterization of the mechanism of heme oxygenase gene activation in response to the substrate heme and stress-associated agents. Regulation of heme oxygenase by heme is the focus of the current proposal. The specific aims of this proposal, which represents a logical extension of the studies carried out in the past three years since the last competitive review, are 1) to define the minimal heme-responsive element (HRE) by mutational analysis: functional and protein binding studies. 2) to isolate and characterize the HRE binding proteins (HRE-BPs) and their corresponding cDNA clones. 3) to determine which HRE-BPs mediate heme responsiveness by inhibition of specific HRE-BP expression (i.e., identification of the heme-response factor). A common feature among heme and other inducers of heme oxygenase is that they generate intracellular oxidative stress. Since pro-oxidants (or oxidative states) have been implicated in a plethora of human pathologies including atherosclerosis, ischemia/reoxy-genation, injury, and cancer, the results from the present studies should further our knowledge of the basic biology of these diseases.