REGULATORY MECHANISMS IN HEPATIC METABOLISM

拟议研究项目的目的是调查 重要的细胞间和细胞内 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。 这种信令 将在完整灌注大鼠肝脏中表征系统 以及在肝衍生细胞的原代培养物中，即，实质， Kupffer和内皮细胞。 我们的研究将提供新的信息 自分泌物质介质的生化机制 在受体介导的免疫细胞内吞作用中的合成 聚集体、酵母聚糖、内毒素和/或其它颗粒物质。 我们将调查涉及的监管机制， 肝实质（肝细胞）对介质的反应 在微粒激发期间产生，并与自体物质介质 直接输注到肝血管中。 这些应对措施 包括明显糖原分解、血管收缩，然后增加 减少耗氧量等，我们将调查 参与氧自由基生成的机制 并寻求使介体合成和/或输注最小化的方法 这种明显的氧化应激的潜在破坏作用 肝脏对急性创伤的反应。 我们的研究 将包括一个仔细的，希望创新的分析细胞 通量使用房室分析和多指示剂稀释 技术在灌注肝脏和分离的细胞制剂。 多磷酸肌醇/肌醇的参与 多磷酸盐/钙信号系统在两种介质产生中的作用 和介体作用机制的特征将在于 分离的培养细胞。 最后，在一个小的研究中，我们将 继续进行我们对甘氨酸调节的研究， 肝脏中的钙离子。 在这项研究中要探索的调节机制可能有 与经典的激素葡萄糖调节信号几乎没有关系 参与肝脏日常维持的系统 碳水化合物代谢 所提出的研究是有意义的 因为它将提供新的重要信息， 肝脏对急性病理生理创伤的反应， 特别是在急性过敏反应或内毒素血症的情况下， 以及在其它慢性病中，在这些慢性病中， 被其他颗粒物质的免疫复合物淹没 其必须被网状内皮系统清除。

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.