REGULATORY MECHANISMS IN HEPATIC METABOLISM

肝脏代谢的调节机制

• 批准号: 3226390
• 负责人: MERLE S OLSON
• 金额: $ 15.54万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-03-01 至 1993-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3226390
• 关键词: Kupffer's cell; NAD(H) phosphate; adenine nucleotides; aminoacid metabolism; anaphylaxis; calcium; eicosanoid metabolism; endotoxins; gluconeogenesis; glucose metabolism; glycine; glycolysis; guinea pigs; high performance liquid chromatography; hormone regulation /control mechanism; inositol phosphates; laboratory rat; leukotrienes; liver cells; liver metabolism; mitochondria; oxygen consumption; perfusion; receptor mediated endocytosis; reticuloendothelial system; tissue /cell culture; vasoconstriction; xanthine dehydrogenase; xanthine oxidase

The objective of the proposed research project is to investigate the mechanistic details of important inter- and intracellular regulatory signaling systems operative in the mammalian liver during acute pathophysiological situations. Such signaling system(s) will be characterized in the intact perfused rat liver and in primary cultures of liver-derived cells, i.e., parenchymal, Kupffer and endothelial. Our studies will yield new information on the biochemical mechanisms involved in autacoid mediator synthesis during receptor-mediated endocytosis of immune aggregates, zymosan, endotoxin and/or other particulate materials. We will investigate the regulatory mechanisms involved in the response of the liver parenchyma (hepatocytes) to mediators generated during particulate challenge and to autacoid mediator infusion directly into the hepatic vasculature. Such responses include pronounced glycogenolysis, vasoconstriction, increased then decreased oxygen consumption, etc. We will investigate the mechanism(s) involved in oxygen radical generation following mediator synthesis and/or infusion and pursue means to minimize the potential damaging effects of this apparent oxidative stress reaction in the liver in response to acute trauma. Our studies will include a careful, hopefully innovative analysis of cellular fluxes using compartmental analysis and multiple indicator dilution techniques in the perfused liver and in isolated cell preparations. The involvement of the polyphosphoinositide/inositol polyphosphate/calcium signalling system in both mediator production and mediator mechanism(s) of action will be characterized in the isolated cultured cells. Finally, in a minor study we will continue to pursue our investigations on the regulation of glycine catabolism in the liver. The regulatory mechanisms to be explored in this study likely have little to do with the classical hormonal glucoregulatory signalling systems involved in the day-to-day maintenance of hepatic carbohdyrate metabolism. The proposed research is significant because it will provide new and important information concerning how the liver responds to acute pathophysiological trauma, especially in situations such as acute anaphylaxis or endotoxemia and also in other chronic conditions during which an individual may be overwhelmed with immune complexes of other particulate material which must be cleared by the regiculoendothelial system.

拟议研究项目的目的是调查 重要的细胞间和细胞内的机制细节 在哺乳动物肝脏中起作用的调节信号系统 在急性病理生理情况下。 这样的信号 将在完整的灌注大鼠肝脏中表征系统 在肝源性细胞（即实质细胞）的原代培养物中， 库普弗和内皮细胞。 我们的研究将产生新信息 关于自体介质涉及的生化机制 受体介导的免疫内吞过程中的合成 聚集体、酵母聚糖、内毒素和/或其他颗粒材料。 我们将研究相关监管机制 肝实质（肝细胞）对介质的反应 在颗粒激发过程中产生并产生自体介质 直接输注到肝血管系统中。 这样的回应 包括明显的糖原分解、血管收缩，然后增加 减少耗氧量等。我们将调查 参与氧自由基产生的机制如下 介体合成和/或输注并寻求最小化的方法 这种明显的氧化应激的潜在破坏性影响 肝脏对急性创伤的反应。 我们的研究 将包括对细胞进行仔细且充满希望的创新分析 使用区室分析和多指示剂稀释的通量 灌注肝脏和分离细胞制剂中的技术。 多磷酸肌醇/肌醇的参与 两种介体产生中的聚磷酸盐/钙信号系统 和调解机制的行动将在 分离培养细胞。 最后，在一项小研究中，我们将 继续进行甘氨酸监管的调查 肝脏中的分解代谢。 本研究要探索的调控机制可能有 与经典的激素葡萄糖调节信号关系不大 涉及肝脏日常维护的系统 碳水化合物代谢。 拟议的研究意义重大 因为它将提供有关以下方面的新的重要信息 肝脏如何应对急性病理生理创伤， 尤其是在急性过敏反应或内毒素血症等情况下 以及其他慢性疾病，在此期间，个人可能 被其他颗粒物质的免疫复合物淹没 必须由血管内皮系统清除。