INVESTIGATIONS INTO THE GLUTAMINE-CITRULLINE-ARGININE PATHWAY IN SEPSIS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 脓毒症是重症监护病房发病率和死亡率的重要原因，报告的死亡率约为20%至50%。由于谷氨酰胺和精氨酸具有重要的生理和代谢作用，是免疫反应的重要调节因子，充足的这两种氨基酸的供应可能是生存的关键，这两种氨基酸都已被用作危重患者的营养补充剂。然而，它们在败血症中的代谢命运仍然没有得到很好的描述。这两种氨基酸通过共同的代谢途径联系在一起，包括谷氨酰胺在肠道内转化为瓜氨酸，然后肾脏摄取瓜氨酸并转化为精氨酸。在这个项目中，我们将量化这两种氨基酸及其中间体瓜氨酸在脓毒症患者与健康对照组中的相互作用。我们认为，在败血症患者中，谷氨酰胺的可获得性以及全身和内脏代谢的改变将导致瓜氨酸和精氨酸的合成减少。稳定同位素示踪方法将被用来检验这些假说的具体方面。具体目标1将确定败血症患者和健康对照组谷氨酰胺转化为瓜氨酸的速率和内脏部分谷氨酰胺提取物的差异。假设是败血症患者从谷氨酰胺合成瓜氨酸减少，瓜氨酸的产生速度与内脏提取谷氨酰胺的速度直接相关。特定目标2将确定败血症患者和健康对照组从其前体瓜氨酸和谷氨酰胺合成从头精氨酸的速率。该假说认为，败血症患者谷氨酰胺供应减少导致从头合成精氨酸减少。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Sepsis is a significant cause of morbidity and mortality in the intensive care unit, with reported mortality rates ranging from approximately 20 to 50 percent. Because glutamine and arginine serve important physiologic and metabolic roles and are important modulators of the immune response, adequate supply of these two amino acids may be critical for survival, and both amino acids have been used as nutritional supplements in critically-ill patients. However, their metabolic fates in sepsis remain poorly characterized. These two amino acids are linked by a common metabolic pathway involving intestinal conversion of glutamine to citrulline followed by renal uptake of citrulline and conversion to arginine. In this project we will quantitate the interplay of these two amino acids along with their intermediate, citrulline, in septic patients compared to healthy controls. We propose that in septic patients, alterations in the availability and whole-body and splanchnic metabolism of glutamine will lead to decreased synthesis of citrulline and arginine. Stable isotope tracer methods will be used to test specific aspects of these hypotheses. Specific aim 1 will determine differences in the rate of glutamine conversion to citrulline and the fractional splanchnic extraction of glutamine in septic patients and healthy controls. The hypothesis is that septic patients have decreased citrulline synthesis from glutamine, and that the rate of citrulline production is directly related to the rate of splanchnic extraction of glutamine. Specific aim 2 will determine the rate of de novo arginine synthesis from its precursors, citrulline and glutamine, in septic patients and healthy controls. The hypothesis is that decreased glutamine availability leads to decreased de novo arginine synthesis in septic patients.