REGULATORY MECHANISMS IN HEPATIC METABOLISM

拟议的研究项目的目标是调查 重要的细胞内和细胞内的机制细节 哺乳动物肝脏中的调节信号系统 在急性病理生理情况下。这样的信号 系统(S)将在完整的灌流大鼠肝脏中表现出来 在肝脏来源细胞的原代培养中，即实质细胞， 库普弗和内皮细胞。我们的研究将产生新的信息 金盏花环类介体的生化机制研究 受体介导的免疫内吞过程中的合成 聚集体、酵母多糖、内毒素和/或其他颗粒物质。 我们将调查涉及的监管机制 肝实质(肝细胞)对介质的反应 在颗粒挑战过程中生成，并传递给奥塔克样介体 直接向肝血管系统输注。这样的反应 包括明显的糖原分解，血管收缩，然后加剧 减少耗氧量等。我们将调查 氧自由基产生的机制(S) 介体合成和/或输注和追求手段，以尽量减少 这种明显的氧化应激的潜在损害效应 肝脏对急性创伤的反应。我们的研究 将包括一个仔细的，希望是创新的细胞分析 使用分室分析和多指示剂稀释的通量 在灌流肝脏和分离细胞制备中的技术。 多磷肌醇/肌醇的参与 多聚磷/钙信号系统在两种介质生产中的作用 而调解人机制(S)的作用将体现在 分离培养的细胞。最后，在一个小研究中，我们将 继续我们对甘氨酸调节的研究 肝脏的分解代谢。 这项研究中要探索的调控机制可能有 与经典的荷尔蒙糖调节信号无关 参与肝脏日常维护的系统 碳酸盐代谢。这项拟议的研究具有重要意义 因为它将提供新的和重要的信息 肝脏对急性病理生理创伤的反应， 尤其是在急性过敏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体淹没 它必须被血管内皮细胞系统清除。

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.