REGULATORY EFFECTS OF HEME TRANSPORT INTO LIVER CELLS

血红素转运至肝细胞的调节作用

• 批准号: 2458772
• 负责人: JAWED ALAM
• 金额: $ 13.16万
• 依托单位: OCHSNER CLINIC FOUNDATION
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-15 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2458772
• 关键词: DNA binding protein; antisense nucleic acid; enzyme induction /repression; enzyme mechanism; gene expression; heme; heme oxygenase; hemopexin; intracellular transport; iron metabolism; liver cells; liver metabolism; molecular cloning; northern blottings; receptor mediated endocytosis; site directed mutagenesis; transcription factor; transfection

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.

描述：血浆糖蛋白的血红素，将血红素传输到肝脏 细胞通过特定的受体介导的过程。 血红素氧酶，a 微粒体膜酶，催化初始和限制步骤 血红素降解。 从血红素释放的铁分子沉积在 铁蛋白簇。 这些蛋白质允许的协同作用 保护生物有用的铁，可防止有毒的积累 血红素分子并抑制入侵微生物的生长。 这 我们研究的长期目标是更好地了解 血红素和铁代谢，尤其强调了血红素的作用 和血红素氧合酶在不良方面保持血红素和铁稳态 疾病（例如，由于遗传性疾病引起的血管内溶血 和/或细菌或病毒感染或由 环境毒素）。 该研究计划的一个方面是 血红素加氧酶基因机理的生化表征 响应底物血红素和应激相关剂的激活。 血红素对血红素加氧酶的调节是当前建议的重点。 该提案的具体目的，代表 自上次竞争激烈的过去三年中进行的研究 评论是1）通过 突变分析：功能和蛋白质结合研究。 2）分离 并表征HRE结合蛋白（HRE-BPS）及其相应 cDNA克隆。 3）确定哪些HRE BP通过 抑制特定的HRE-BP表达（即鉴定 血红素反应因子）。 血红素氧化酶的血红素和其他诱导剂之间的共同特征是 它们产生细胞内氧化应激。 由于促氧化剂（或 氧化态）与许多人体病理有关 包括动脉粥样硬化，缺血/再氧发射，损伤和癌症， 本研究的结果应进一步我们对基本的了解 这些疾病的生物学。